F

F2 Intercross

Definition

The second-generation descendents of a cross of

two contrasting populations (e.g., inbred strains).The offspring of the cross (i.e., F1 hybrids) are

sib-mated to produce F2 hybrids, in which homol-

ogous recombination has “shuffled” the genomesof the progenitors in a unique manner. F2 hybrids

from inbred strain progenitors are useful for

quantitative trait locus (QTL) mapping.

Cross-References

▶Quantitative Trait Locus Mapping

Fabry’s Disease

▶Metabolic and Nutritional Neuropathies

Faces Pain Scale

Definition

Visual pain scale of seven faces now tested in

older adults as well as children.

Cross-References

▶Cancer Pain, Assessment in the CognitivelyImpaired

Facet Denervation

▶ Facet Joint Procedures for Chronic Back Pain

Facet Joint

Definition

Facet is a flat, platelike surface that acts as part of

a joint, as seen in the vertebrae of the spine and in

the subtalar joint of the ankle. Each vertebra hastwo superior and two inferior facets. Facet joints

are small stabilizing synovial joints located

between and behind adjacent vertebrae.

Cross-References

▶Chronic Back Pain and Spinal Instability

▶Chronic Low Back Pain: Definitions andDiagnosis

▶ Facet Joint Pain

▶ Pain Treatment: Spinal Nerve Blocks

G.F. Gebhart, R.F. Schmidt (eds.), Encyclopedia of Pain, DOI 10.1007/978-3-642-28753-4,# Springer-Verlag Berlin Heidelberg 2013

Facet Joint Injection

▶ Facet Joint Procedures for Chronic Back Pain

Facet Joint Pain

Jenna E. Zauk1, Alfred T. Ogden2 andChristopher J. Winfree2

1St. George’s University, School of Medicine,

Grenada, West Indies2Department of Neurological Surgery,

Neurological Institute Columbia University,

New York, NY, USA

Synonyms

Facet syndrome; Sciatica; Zygapophysial joint

pain

Definition

Although the intervertebral joint has long been

known to be a common generator of low backpain and leg pain, the facet joint has been

proposed as another potential focus of degenera-

tive pathology that can produce similar symp-toms. Structurally analogous to joints in the

extremities, the facet joint has the capacity todegenerate over time and cause pain through the

same mechanisms that are at play in osteoarthritis

of the hip or the knee. This pain can be “felt” bythe patient in the area of the facet, producing low

back pain, or it can potentially be referred to other

parts of the body through the activation ofadjacent nociceptive fibers. Radiofrequency,

cryoneuroablation, and chemical neurolysis are

all possible treatment modalities for lumbar facetsyndrome (Wheeler and May 2010). Although

a “facet syndrome” including a component of

sciatica was initially proposed, stimulation ofthe nerve supply to facet joints in live subjects

has shown reproducible patterns of pain that are

limited to the low back, flank, abdomen, and

buttock. Many studies have claimed a benefitfrom treatment of low back pain through inter-

ventions aimed at disrupting the primary affer-ents supplying the facet joint, but the handful of

randomized clinical trials of these interventions

has generally failed to demonstrate any benefitbeyond placebo (Carette et al. 1991; Leclaire

et al. 2001; Lilius et al. 1989, Slipman 2003).

These studies have been criticized, however,and their generally negative results may stem

from poor patient selection and improper selec-

tion of therapeutic target. In 2009, a panel ofexperts in interventional therapies and surgery

recommended against the use of facet joint

steroid injections as a treatment for lower backpain. Their decision was based upon insufficient

evidence from previously conducted studies

(Chou et al. 2009b). Although rates of use forfacet joint injections increased by 231 % from

1994 to 2001, these therapies have shown to only

improve short-term pain management (Friedlyet al. 2007; Chou et al. 2009a).

Characteristics

Anatomical ConsiderationsGhormley is credited with coining the phrase the

“facet syndrome” in 1933 (Ghormley 1933).

In his seminal article, he noted that facet jointswere the only “true” joints in the spinal column,

meaning that they contain a complete joint cap-

sule with a clear synovial membrane and hyalinecartilage at the articular surface. Such true joints

are termed zygapophysial joints and exist in all

the typical weight-bearing places affected byosteoarthritis such as the hip, the knee, and the

ankle. He conjectured and offered histopatholog-

ical evidence that these joints degenerate overtime like their counterparts in the extremities.

He theorized that this process could produce

a syndrome of low back pain, scoliosis, andsciatica, perhaps induced by rotatory strain of

the lumbosacral region.

Detailed anatomical studies of the nerve sup-ply of facet joints have provided the blueprint for

testing and treating the “facet syndrome.”

Each joint is innervated by spinal nerves from

F 1246 Facet Joint Injection

the adjacent and superior vertebral level on theipsilateral side (Bogduk and Long 1979;

Maldjian et al. 1998; Mooney and Robertson1976). Arising from the dorsal root ganglion,

the medial branch of the posterior ramus passes

through a notch at the base of the transverseprocess. Twigs are given off to the facet joint at

the same level before the nerve descends inferi-

orly, giving off muscular and cutaneousbranches, as well as a branch to the superior

aspect of the facet joint one vertebral level

below. Bogduk and Long published the mostdetailed anatomical study of these relationships,

and proposed calling the branches comprising

this dual nerve supply the proximal and distalzygapophysial nerves (Bogduk and Long 1979).

These same authors recognized variability at

L5–S1 mandated by the absence of transverseprocesses at this level, and noted the medial

branch of the posterior ramus of L5 passes

through a groove between the sacral ala and theroot of the superior articular process of the

sacrum. The key points from this anatomical

study were that denervation of a facet jointwould require a lesion of the medial branch of

the posterior ramus at the same vertebral level

and the level above, and that a denervation pro-cedure directed at the facet joint proper might

result in an incomplete lesion.

Provocative StudiesThe first report of nervous stimulation of facet

joints that induced back and leg pain was byHirsch et al. in 1963 (Hirsch et al. 1963). The

first systematic analysis of referred lumbar

facet joint pain was written by Mooney andRobertson in 1975 (Mooney and Robertson

1976). These authors studied five normal sub-

jects and 15 patients with low back pain, andreported a nonspecific pattern of pain referral

to the flank, buttock, and the leg upon injec-

tion of 5 % hypertonic saline into the facetjoint. An important discrepancy was noted

between normal and low back pain patients

in that the latter complained of more frequentand more widespread patterns of pain referral.

The only reports of induced pain in a sciatic

distribution came from the low back pain

cohort. These authors also related their resultswith fluoroscopically guided anesthetic injec-

tions, and offered a detailed description of theprocedure, which served as a model for future

studies. Due to difficulty in locating the pre-

cise vertebral level of the pain generator,injections at three lumbar levels were advo-

cated and injections were directed into the

facet joint proper. The facet joint, as the targetof treatment, has been used by many clinicians

and in many studies ever since, but this

approach has come under criticism by some,who maintain that a more efficacious target of

anesthetization or neurotomy is the medial

branch of the posterior ramus (Bogduk andLong 1979).

The technique of Mooney and Robertson

was applied (McCall et al. 1979) to six healthyindividuals who received fluoroscopically

guided injections of 6 % hypertonic saline into

lumbar facet joints of L1–2 and L4–5. Theynoted several important findings. L1–2 injec-

tions reproduced pain to the adjacent lower

back, flank, and groin. L4–5 injections pro-duced pain in the adjacent lower back, buttock,

groin, and lateral thigh. There was significant

overlap in the distribution of the patterns ofreferred pain, even though the facet joints

selected were three levels apart, and there was

no patient that complained of pain below themid-thigh.

Provocative studies have shown fairly clearly

that stimulation of the sensory nerves aroundfacet joints can induce pain, and that this stimu-

lation can reproducibly generate pain that is

referred to other parts of the body. It is stillunclear to what extent this induced pain has

a relationship to the clinical entity of low back

pain in the general population. The paucity ofprovocative evidence for the induction of

referred leg upon stimulation of facet joints in

control populations casts some doubt on thesciatic component of the alleged “facet syn-

drome.” The lack of dermatomal specificity for

referred pain from facet joint stimulation mayreflect the dual level innervation, and contribute

to the difficulty in localization of the potential

pain-generating level.

Facet Joint Pain 1247 F

F

Randomized Clinical TrialsThere have been multiple studies of treatments

for facet joint pain including both anesthetic and

steroid injections and radiofrequency nerveablations. These studies vary greatly in their

selection criteria and reported results. For exam-

ple, reported efficacy of facet joint steroid injec-tion ranges from 10 % to 63 % (Carette et al.

1991). The vast majority of these studies are

retrospective case series. These divergent resultslikely stem from variable selection criteria,

variable technique and target selection, variable

follow-up, and variable criteria for a successfultreatment. As such, they are very difficult to

interpret. One review of these studies found

“sparse evidence” to support the use of interven-tional techniques in the treatment of facet joint

pain, and called for more randomized clinical

trials (Slipman 2003).Four peer-reviewed randomized clinical tri-

als for the treatment of low back pain through

facet joint procedures have been published, andthe conclusion from three out of four of these

studies was that no treatment has demonstrated

any benefit beyond placebo (Carette et al. 1991;Leclaire et al. 2001; Lilius et al. 1989; van Kleef

et al. 1999). There are criticisms of each study,

however, which could have significantlyaffected results, and these criticisms are

discussed below.In 1989, Lilius et al. (Lilius 1989) random-

ized 109 patients with low back pain to receive

injections of cortisone, local anesthetic, orsaline into two facet joints. Patients were exam-

ined at 1 hour, 2 weeks, and 6 weeks, and also

filled out a questionnaire regarding work per-formance and pain level at 3 months. Seventy

percent of patients experienced initial pain

relief and 36 % of patients reported continuedbenefit at 3 months. These results were

irrespective of the contents of the injection.

The major flaw in this study was that therewere no selection criteria beyond low back

pain to ensure that the facet joints were the

pain generators in these patients. Another criti-cism was that the facet joint was used as the

therapeutic target and not the medial branch of

the posterior ramus.

In 1991, Carette et al. (Carette 1991) random-ized 97 patients who reported >50 % immediate

relief from low back pain following local anes-thetic injection into facet joints, both at L4–5 and

at L5–S1, to receive either steroid injections or

saline injections. They followed the techniquedescribed by Mooney and Robertson (i.e., fluoro-

scopic guidance using contrast to localize the

facet joint and injection into the facet jointproper). Patients were assessed immediately

following the procedure and at 1-, 3-, and

6-month follow-up intervals. They found that 11patients in the steroid group and 5 patients in the

saline group had prolonged relief from the injec-

tions. The difference was not statistically signif-icant. A post-hoc analysis of the subgroup of

patients who claimed >90 % relief from the

initial anesthetic injections yielded similarresults. As mentioned previously, the target

selection according to the technique of Mooney

and Robertson has been criticized. It is also nota-ble that their results approached significance

(p ¼ 0.19), begging the question of whether

their study was simply underpowered.In 1999, van Kleef et al. (van Kleef 1999)

randomized 31 patients selected for>50 % relief

from facet nerve block to receive radiofrequencynerve ablation or sham treatment. These authors

targeted the medial branch of the posterior ramus

according to the description of Bogduk and Long.Patients were assessed immediately after the pro-

cedure and at 1-, 3-, 6-, and 12-month intervals.

Although initial analysis of their patient popula-tion showed no statistically significant benefit of

radiofrequency ablation over placebo, a post-hoc

analysis of the patients that reported the mostrelief from screening anesthetic injections dem-

onstrated a benefit from the procedure. The

authors concluded that this subpopulation ofpatients were the true sufferers of facet joint

pain and that these patients, when properly

selected, would benefit from radiofrequencyneurotomy.

In 2001, Leclaire et al. (Leclaire 2001)

randomized 70 patients selected for “significant”relief of low back pain after two level anesthetic

injections. The target selected was the facet joint

itself. Patients were assessed at 4 weeks and at

F 1248 Facet Joint Pain

12 weeks using two measures of functionalabilityand one pain scale. Although one of the func-

tional assessments showed a small but statisti-cally significant improvement in the treatment

group at 4 weeks, there were no statistically

significant differences in the other functionalassessment or the pain assessment at 4 weeks, or

in any of the outcome measures at 12 weeks. The

authors concluded that beyond a mild transientreduction in functional disability, radiofrequency

facet joint neurotomy had no proven benefit in the

treatment of low back pain. No post-hoc analysisof the patients who were most relieved by the

selecting anesthetic injections was done. This

study was criticized for its vague selectioncriteria and for its use of the facet joint as

a target (Dreyfuss et al. 2002).

In 2005, Fuchs et al. (Fuchs 2005) randomized60 patients suffering from chronic lumbar pain in

a blind-observer clinical trial to evaluate the ther-

apeutic results of intra-articular sodiumhyaluronate (SH) injections versus glucocorti-

coid (TA) injections. The patients were divided

into two groups to be treated with either 10-mgSH or 10-mg TA. The injections were delivered

per facet joint bilaterally (from L3-S1) on a

weekly basis. Level of pain was determined bythe Visual Analog Scale (VAS), and life quality

was determined by the Roland Morris question-

naire, Oswestry Disability questionnaire, LowBack Outcome Score and the Short Form 36

(SF-36) questionnaire. Throughout the 180-day

trial period, both groups of patients demonstratedincreased positive results in pain relief and qual-

ity of life. As for long-term results (>6 months),

the sodium hyaluronate injections were poten-tially more beneficial for patients when compared

to the glucocorticoid injection therapy (Fuchs

et al. 2005).While the existence of a “facet syndrome”

that includes sciatica seems unlikely,

a syndrome of low back pain caused by degen-erative changes in the facet joints seems plau-

sible. Provocative studies of sensory nerves to

facet joints, as well as the close anatomicalassociation between the nervous supply to the

facet joint and the dorsal root ganglion, pro-

vide evidence of a pattern of referred pain to

areas as distant as the buttocks and inguinalregion. The prevalence of this entity within

the vast population of patients with low backpain remains unknown.

Randomized clinical trials have failed to

demonstrate convincing data to justify facetjoint steroid injections or radiofrequency

neurotomy within the populations of patients

studied, but these results could easily be theresult of improper patient selection. In the

absence of a reliable radiographic diagnostic

tool, more stringent screening criteria arerequired before these procedures should be

dismissed. The cut-off of >50 % pain relief

after a single session of anesthetic injectionsused by the studies reviewed may be too liberal

and/or too unreliable. One interesting study

probed this issue. Starting with 176 patientswith low back pain, 47 were selected that

reported a “definite” or “complete” response

after facet block with a short-actinganesthetic. When this cohort was brought back

for a confirmatory block 2 weeks later, only

15 % reported >50 % response (Schwarzer1994). Facet joint degeneration may thus be

a relatively rare cause of low back pain. Perhaps,

anesthetic injections are simply not a reliablescreening tool. Also, the difficulty to locate the

exact site of the pain is a common problem in

injection therapy (Fuchs et al. 2005). Anotherexplanation for the negative results from clinical

trials may lie in target selection. It has yet to be

determined whether the facet capsule or themedial branch of the posterior ramus is pre-

ferred. Only randomized trials of steroid injec-

tions or ablation procedures that use morestringent selection criteria and compare results

using different therapeutic targets will answer

these questions.

References

Bogduk, N., & Long, D. M. (1979). The anatomy of theso-called “Articular Nerves” and their relationship tofacet denervation in the treatment of low-back pain.Journal of Neurosurgery, 51, 172–177.

Carette, S., Marcoux, S., Truchon, R., et al. (1991).A controlled trial of corticosteroid injections into

Facet Joint Pain 1249 F

F

facet joints for chronic low back pain. The NewEngland Journal of Medicine, 325, 1002–1007.

Chou, R., Atlas, S., Stanos, S., & Rosenquist, R. (2009a).Nonsurgical interventional therapies for low backpain, a review of the evidence for an American painsociety clinical practice guideline. Spine, 34(10),1078–1093.

Chou, R., Loeser, J., Owens, D., Rosenquist, R., Atlas,S., Baisden, J., Carragee, E., Grabois, M., Murphy,D., Resnick, D., Stanos, S., Shaffer, W., & Wall, E.(2009b). Interventional therapies, surgery, andinterdisciplinary rehabilitation for low back pain,an evidence-based clinical practice guideline fromthe American pain society. Spine, 34(10), 1066–1077.

Dreyfuss, P., Baker, R., & Leclaire, R. (2002).Radiofrequency facet joint denervation in the treat-ment of low back pain: A placebo-controlled clinicaltrial to assess efficacy. Spine, 27, 556–557.

Friedly, J., Chan, L., & Deyo, R. (2007). Increase inlumbosacral injections in the medicare population.Spine, 32, 1754–1760.

Fuchs, S., Erbe, T., Fischer, H. L., & Tibesku, C. O.(2005). Intraarticular hyaluronic acid versus glucocor-ticoid injections for nonradicular pain in the lumbarspine. Journal of Vascular and InterventionalRadiology, 16(11), 1493–1498.

Ghormley, R. K. (1933). Low back pain: With specialreference to the articular facets. Journal of theAmerican Medical Association, 101, 1773–1777.

Hirsch, D., Ingelmark, B., & Miller, M. (1963). The ana-tomical basis for low back pain. Acta OrthopaedicaScandinavica, 33, 1.

Leclaire, R., Fortin, L., Lambert, R., Bergeron, Y. M., &Rossignol, M. (2001). Radiofrequency facet jointdenervation in the treatment of low back pain:A placebo-controlled clinical trial to assess efficacy.Spine, 26, 1411–1417.

Lilius, G., Laasonen, E. M., Myllynen, P., Harilainen, A.,& Gronlund, G. (1989). Lumbar facet joint syndrome.A randomised clinical trial. Journal of Bone and JointSurgery, 71, 681–684.

Maldjian, C., Mesgarzadeh, M., & Tehranzadeh, J. (1998).Diagnostic and therapeutic features of facet and sacro-iliac joint injection. Anatomy, pathophysiology, andtechnique. Radiologic Clinics of North America, 36,497–508.

McCall, I. W., Park, W. M., & O’Brien, J. P. (1979).Induced pain referral from posterior lumbar elementsin normal subjects. Spine, 4, 441–446.

Mooney, V., & Robertson, J. (1976). The facet syndrome.Clinic Orthopaedics and Related Research, 1976, 115,149–156.

van Kleef, M., Barendse, G. A., Kessels, A., Voets, H. M.,Weber, W. E., & de Lange, S. (1999). Randomizedtrial of radiofrequency lumbar facet denervation forchronic low back pain. Spine, 24, 1937–1942.

Wheeler, A. H. May 2010 – http://emedicine.medscape.com/article/1144130-overview

Facet Joint Procedures for ChronicBack Pain

David M. Sibell

Comprehensive Pain Center/Spine Center,

Oregon Health and Science University, Portland,OR, USA

Synonyms

Facet denervation; Facet joint injection; Facetrhizolysis; Medial branch block; Median branch

block; Radiofrequency ablation; Zygapophyseal

joint injection; Zygapophysial joint injection

Characteristics

Zygapophyseal (facet) joints are synovial diar-

throses and are present from C1 to S1, inclusive.

These joints allow for articular motion in theposterior spinal column and are innervated by

medial branch of the primary posterior ramus ofthe segmental spinal nerves. Each articular pro-

cess receives innervation from a spinal nerve, so

each joint, comprised of two articular processes,is innervated by two medial branches (Fig. 1).

The medial branch is primarily sensory to the

joint and surrounding structures and is innervatedrichly with nociceptive fibers. Numerous pain-

mediating neurotransmitters (e.g., bradykinin,

substance P, and neuropeptide Y) are alsofound in these neurons (Morinaga et al. 1996).

These nerves are also motor to the multifidus

muscles, and multifidus EMG studies have beenused to validate the results of radiofrequency

medial branch denervation (Dreyfuss et al. 2000).

Initially, the approach to treating facetarthropathy-related pain was limited to surgical

excision and/or stabilization. It is difficult to

assess the results of the surgical approaches tofacet arthropathy, as patients do not uniformly

have diagnostic procedures first, and the surgical

treatment is almost always a part of anothersurgical procedure (e.g., fusion, laminectomy).

F 1250 Facet Joint Procedures for Chronic Back Pain

Joint injections with local anesthetic andsteroid are still popular in many practices, but

these injections have not been demonstrated to

be reliably diagnostic (due to potential epiduralspread of injectate) or of any prolonged thera-

peutic value (Dreyfuss and Dreyer 2003).

Numerous prospective, double-blinded, random-ized controlled trials have shown these injections

to be no better than placebo in the treatment ofchronic back and neck pain (Barnsley et al. 1994;

Carette et al. 1991). There have been no signifi-

cant studies since these indicate that there isa role for intraarticular steroid injections.

Fluoroscopically guided diagnostic medial

branch blocks anesthetize the facet joint selec-tively and are used to provide prognostic infor-

mation for radiofrequency medial branch

denervation. They are not intended for prolongedanalgesia. Generally, a two-block paradigm is

used: one injection of short-acting local

anesthetic and one of long-acting anesthetic(Lord et al. 1995). When performed correctly,

these blocks have high specificity for anesthetiz-

ing the facet joint (Dreyfuss et al. 1997)(Figs. 2 and 3). Some authors have attempted to

use ultrasound as guidance for this procedure,

and in ideal settings, it is possible that theremay be a role. However, in clinical practice,

body habitus and the inability to detect intravas-

cular injections or perform injections at morethan one site at a time will remain significant

barriers (Rauch et al. 2009).

There has been debate regarding the exactinterpretation of these blocks, fueled by the prob-

lems inherent in attempting to make an objective

diagnosis in a subjective disorder (i.e., pain).Much of this debate has focused on the test

characteristics of the procedure and uses termssuch as “placebo response” and “false positive”

Facet Joint Procedures for Chronic Back Pain,Fig. 2 Lumbar medial branch block AP view with local-ized spread of contrast medium

Facet Joint Procedures for Chronic Back Pain,Fig. 1 Illustration of right posterior view of lumbosacralspine showing key right posterior neural structures. L2through S1 spinous processes labeled. Right:MB1 medialbranch of L1 dorsal primary ramus, NR2 L2 nerve root,DPR2 L2 dorsal primary ramus, LB2 lateral branch of L2dorsal primary ramus, TP3 L3 transverse process, NR3 L3nerve root,MBmedial branch of L3 dorsal primary ramusthat extends around the base of the right superior articularprocess (S) of L4 and innervates portions of the right L3–4and L4–5 facet joint capsules, NR4 L4 nerve root, IC iliaccrest, DPRL5 L5 dorsal primary ramus, DPRS1 S1 dorsalprimary ramus, I inferior articular process L3, S superiorarticular process of L4. Left: FJ L2–3 facet(zygapophysial) joint, which is innervated by branchesof L1 and L2 medial branch nerves, IAB inferior articularbranches from medial branch of L4 dorsal primary ramus,SAB superior articular branches from medial branch of L4dorsal primary ramus (FromCzervionke and Fenton 2003)

Facet Joint Procedures for Chronic Back Pain 1251 F

F

(Barnsley et al. 1993). Unfortunately, these terms

are misleading in this sense. A subject may have

an unanticipated response to an injection, but ifan active treatment is used, by definition, that

response is not a placebo response. Moreover, it

is inappropriate to use the term “false positive” inthis situation, as there is no gold standard test

with which to compare the results.

These studies do not take into account theanalgesic effect that simultaneously anesthetiz-

ing the multifidus muscle has, which may

account for the prolonged duration of somesubjects’ responses. Therefore, since this field

deals with subjective responses, most operators

use a somewhat more liberal interpretation ofthe results of diagnostic medial branch blocks

and allow for prolonged concordant responses

(i.e., both responses more prolonged thanwould be expected solely due to the local anes-

thetic but of duration proportional to the antic-ipated duration). In addition, multifidus is

denervated by the radiofrequency denervationprocedure, but there are no long-term sequelae

(Dreyfuss et al. 2009).Once the diagnosis of painful facet arthropa-

thy is made, radiofrequency facet denervation is

the minimally invasive treatment of choice.This technique has been used over the last four

decades and has advantages in the treatment of

facet arthropathy over other neurolytictechniques, such as chemodenervation or

cryotherapy. As the technology and techniques

have improved, prospective studies have dem-onstrated efficacy in select groups, although

there has been some lack of uniformity among

these results (Dreyfuss et al. 2002; Niemistoet al. 2003; Slipman et al. 2003). There has

been one prospective study of lumbar

radiofrequency medial branch denervation thatproduced negative (non-difference from pla-

cebo) results (van Wijk et al. 2005). However,

the technique in this study was non-standard,and other authors in this field have challenged

the results, as the technique was likely to miss

the target nerve (Bogduk 2006). Since then, sev-eral studies have demonstrated positive results,

though there is still a need for a large, multicen-

ter, prospective, randomized trial (Nath et al.2008; Burnham et al. 2009).

The technique involved in radiofrequency

facet denervation is similar to that of medialbranch blocks, inasmuch as the instrument is

placed in proximity to the medial branches inner-

vating a joint, as opposed to entering the jointitself (Lau et al. 2004). However, instead of using

plain needles, special cannulae are used. These

are coated with heat-shrink Polyethylene Tere-phthalate (PET) tubing in order to insulate most

of the needle. This focuses the release of

radiofrequency energy on the active tip, whichleads to a focused, reproducible lesion. When

positioned appropriately, this lesion includes the

medial branch, while limiting collateral damageto surrounding structures. As a result of this pre-

cision, the risk of adverse events is exceedingly

low (Kornick et al. 2004). The safety profile isone of the features that make this procedure an

attractive alternative in the treatment of this

common disorder.

Facet Joint Procedures for Chronic Back Pain,Fig. 3 Lumbar medial branch block lateral oblique view

F 1252 Facet Joint Procedures for Chronic Back Pain

The desired outcome in this procedure is thefocal denervation of the joints in which the

patient’s back pain was relieved upon perfor-mance of diagnostic medial branch blocks. This

does not treat the underlying arthropathy but

reduces the painful limitation to mobility that itcauses. The nature of radiofrequency denervation

does allow for regrowth of the medial branch

nerve. Therefore, the procedure may requirerepetitive treatments over time. Longer-term

cohorts and studies of repeated intervention

indicate that the clinical results of the procedurelast approximately 12 months, which is consis-

tent with a period of denervation, followed

by regrowth of the medial branch nerve(Tome-Bermejo et al. 2011; Rambaransingh

et al. 2010). Since the denervation procedure

does not address comorbidities, such asmyofascial pain, post-denervation physical ther-

apy may be used to extend the benefits of the

procedure, to include relief of myofascial painand associated loss of range of motion.

Due to the increasing use of this procedure in

the United States (Friedly et al. 2007), insurershave sought to limit its availability by placing

stringent requirements on patients with

facetogenic pain prior to approvingradiofrequency medial branch denervation

(Noridian Local Coverage Determination; United

Health Care Medical Policy). While the datasupporting this procedure are imperfect, there is

only one significant negative study, which used

a nonstandard technique. The weight of evidencefor the positive symptomatic and functional

effects of radiofrequency medial branch denerva-

tion is far greater than for most analgesic inter-ventional procedures. It remains to be seen

whether this useful, safe procedure will continue

to be available to those who most benefit fromits use.

References

Barnsley, L., Lord, S., Wallis, B., et al. (1993). False-positive rates of cervical zygapophysial joint blocks.The Clinical Journal of Pain, 9, 124–130.

Barnsley, L., Lord, S. M., Wallis, B. J., et al. (1994). Lackof effect of intraarticular corticosteroids for chronic

pain in the cervical zygapophyseal joints. The NewEngland Journal of Medicine, 330, 1047–1050.

Bogduk, N. (2006). Lumbar radiofrequency neurotomy.The Clinical Journal of Pain, 22(4), 409.

Burnham, R. S. MSc, MD, FRCPC, Holitski, S. BScPT, &Dinu, I. PhD. (2009). A prospective outcome study onthe effects of facet joint radiofrequency denervation onpain, analgesic intake, disability, satisfaction, cost, andemployment. Archives of Physical Medicine andRehabilitation, 90, 201–205.

Carette, S., Marcoux, S., Truchon, R., et al. (1991).A controlled trial of corticosteroid injectionsinto facet joints for chronic low back pain.The New England Journal of Medicine, 325,1002–1007.

Czervionke, L. F., & Fenton, D. S. (2003). Facet jointinjection and medial branch block. In L. F. Czervionke& D. S. Fenton (Eds.), Image-guided spine interven-tion. Philadelphia: WB Saunders.

Dreyfuss, P., & Dreyer, S. J. (2003). Lumbarzygapophysial (facet) joint injections. The SpineJournal, 3, 50S–59S.

Dreyfuss, P., Schwarzer, A. C., Lau, P., et al. (1997).Specificity of lumbar medial branch and L5 dorsalramus blocks. A computed tomography study. Spine,22, 895–902.

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Facet Rhizolysis

▶ Facet Joint Procedures for Chronic Back Pain

Facet Syndrome

▶ Facet Joint Pain

Facial Ganglion Neuralgia

▶Geniculate Neuralgia

Facial Pain

Definition

Facial pain is identified by its location, usually

excluding tic douloureux.

Cross-References

▶ Pain Treatment, Motor Cortex Stimulation

Facial Pain Associated withDisorders of the Cranium

▶Headache from Cranial Bone

Facilitative Tucking

Definition

A caregiver uses his/her hands to swaddle aninfant by placing a hand on the infant’s head

and feet while providing flexion and

containment.

Cross-References

▶Acute Pain Management in Infants

F 1254 Facet Rhizolysis

Factor Loading

Definition

Factor analysis is a statistical procedure that

groups together variables that share common var-iance. Variables that “load” on the same factor

are presumed to reflect a similar underlying

process.

Cross-References

▶ Psychology of Pain, Self-Efficacy

Factors Associated with LowBack Pain

▶Low Back Pain, Epidemiology

Failed Back

Definition

Clinical syndrome characterized by back or lower

extremity pain or both following surgery fordecompression of neural elements in the lower

back.

Cross-References

▶ Pain Treatment: Spinal Cord Stimulation

Failed Back Surgery Syndrome

Definition

Failed back surgery syndrome is axial or radicu-

lar pain persisting after surgical approaches to

relieve the pain. It is also known as failed backsyndrome.

Cross-References

▶Central Nervous System Stimulation for Pain

▶Dorsal Root Ganglionectomy and Dorsal

Rhizotomy

False Affirmative Rate

Definition

False affirmative rate is the probability of

response “A” when event B has occurred.

Familial Adenomatous Polyposis

Synonyms

FAP

Definition

An inherited disease which is characterized by

the formation of numerous polyps on the inside

walls of the colon and rectum. The FAP disease isassociated with a 100 % risk for developing colo-

rectal cancer.

Cross-References

▶NSAIDs and Cancer

Familial Amyloid Polyneuropathy(FAP)

▶Hereditary Neuropathies

Familial Amyloid Polyneuropathy (FAP) 1255 F

F

Familial Factors

▶ Impact of Familial Factors on Children’sChronic Pain

Familial Hemiplegic Migraine

Definition

Familial hemiplegic migraine is an inherited

form of migraine with aura in which patients

experience weakness and other neurological dis-turbances as their aura.

Cross-References

▶Migraine, Pathophysiology

Familial Polyposis Coli

Definition

People with this syndrome have massive numbersof colonic polyps and almost invariably develop

cancer of the colon.

Cross-References

▶NSAIDs and Their Indications

Family Environment

▶ Impact of Familial Factors on Children’sChronic Pain

Family-Centered Care

Lisa M. PetersDepartment of Anesthesiology and Pain

Medicine, Seattle Children’s Hospital, Seattle,

WA, USA

Synonyms

Family-centered theory; Patient-centered care

Definition

What Is Family-Centered Care?The practice of pediatrics focuses on the health

of a child. The experience of pediatric care, how-ever, is not isolated to the child; the experience

impacts the whole family. In fact, a bidirectional

relationship exists whereby efforts to provideholistic care to a child necessarily involve

accounting for relevant contextual factors.

Context includes elements internal to the child,such as developmental level, as well as external

to the child, such as familial influences. The

method and degree to which this relationship isembraced in the care setting is the focus of an

approach called family-centered care.While the central tenants of family-centered

care may be practiced to varying degrees around

the world, most of the published literature on thistopic has originated from the United States

and United Kingdom in the last two decades.

Definitions articulate an approach to decisionmaking and information sharing, captured most

powerfully in one word, partnership. Together,

healthcare practitioners, patient, and familynavigate each step along the care pathway with

intention and respect.

A framework for family-centered care inpediatrics, originally described by Shelton in

1987, includes the following nine elements:

• Recognizing the family as a constant in thechild’s life

F 1256 Familial Factors

• Facilitating parent-professional collaboration

at all levels of health care• Honoring the racial, ethnic, cultural, and

socioeconomic diversity of families

• Recognizing family strengths and individualityand respecting different methods of coping

• Sharing complete and unbiased informationwith families on a continuous basis

• Encouraging and facilitating family-to-family

support and networking• Responding to child and family developmen-

tal needs as part of healthcare practices

• Adopting policies and practices that providefamilies with emotional and financial

support

• Designing health care that is flexible, cultur-ally competent, and responsive to family

needs

According to the Institute for Family-Centered Care, established in 1992 in the USA,

the summary themes include: respect and dignity;

information sharing; participation; and collabo-ration (Committee on Hospital Care. American

Academy of Pediatrics & Institute for Patient-

and Family-Centered Care, 2003).

Characteristics

Pediatric Pain and Family-Centered CarePain in children is complex. Yet, the fundamen-tal human right to pain care drives the field to

further scientific study and the individual prac-

titioner to prevent and alleviate children’s pain.From parents’ perspective, data show that the

top two (among 36) issues of priority for their

children admitted to an acute care setting were“Find out what is wrong with my child” and

“taking care of my child’s pain if it is relevant.”

And yet, pain presented the greatest discrepancybetween priority and level of satisfaction

(Ammentorp 2005). Through the alignment of

science and humanity, the greatest possibleimpact on the short- and long-term conse-

quences of poorly treated or untreated pain in

children can be realized. Therein lays the

synergy of a family-centered care approach toimprove a child’s experience with pain;

a partnership of evidence-based health care andthe expertise of self-report or parents’ knowl-

edge of their child.

Clinical: A Call to Action

A commitment to partner along the clinical care

continuum particularly illustrates the powerfulopportunity, including assessment, planning,

intervention, and evaluation. First, the corner-

stone of effective pain care is assessment. Evolu-tion of study has led to an iterative set of

developmental-age specific tools to assess the

intensity of children’s pain. However, healthcarepractitioners are not treating an intensity number,

they are treating a person. Thus, it becomes

essential to engage a parent to share and observebehavioral cues noticed in their child, or honor an

adolescent’s self-report of the quality, location,

duration, and aggravating and relieving factors(Reid et al. 1995). From the outset, it must be

noted that communication is foundational and

continuous (Garland and Kenny 2006). Thus,eliminating language disparity via routine and

readily accessible interpreter services is critical

(Guerrero et al. 2010). This exchange informsplanning for pain care and draws upon the critical

component of respect. The well-recognized, pos-

itive effects of an interdisciplinary approach topain care match the collaborative model of fam-

ily-centered care (Huth et al. 2003; Shields et al.

2006; Simons et al. 2001). This is an opportunityto welcome and optimize a family’s strengths and

an individual child’s coping style. The impor-

tance of optimizing patient and parent participa-tion and coping has been clearly demonstrated,

such as in a cohort of adolescents with sickle cell

disease (Mitchell 2007). A partnership to shareinformation allows for unbiased presentation of

evidence-based interventions and nonjudgmental

discussion. It becomes essential to recognize thatall parties may hold different elements of the care

at a premium, including evaluation of the risk and

benefit of the pain experience itself, as well as theinterventions and goals.

Family-Centered Care 1257 F

F

Education: Empowering AdvocatesEfforts to enhance awareness and knowledge of

children’s pain through education can give new

voice to all. Education offers a link to close thegap between the prevalence of undertreated or

untreated pain in children and the lack oftimely, effective interventions to prevent or

alleviate that pain. In its 2011 publication titled

“Relieving Pain in America,” the Institute ofMedicine cites education as a foundational

endeavor to transform care (IOM 2011). The

aim of educational activities may focus onexpectations and current evidence of pain care

to inform a shared mental model, yet impor-

tantly also focus on the benefit of each mem-ber’s individual expertise. In other words, to

recognize that a healthcare provider has the

responsibility to contribute expertise in currentevidence-based treatment options, while

a parent has the responsibility to contribute

expertise in their child’s context and currentexperience. Such messaging again emphasizes

communication as key; there is support for any-

one to speak up and advocate on behalf ofa child, including truly creating space for and

hearing the voice of a parent.

Research: Data to Improve Outcomes

In recent years, further collaboration between

the scientific community and the healthcareconsumer offers another example of, and

opportunity for, a powerful partnership

(MacKean et al. 2005). For example, the Patient-Centered Outcomes Research Institute (PCORI) is

an independent, nonprofit organization in the USA

created to contribute specifically to shared,informed decision making by patients, families,

and healthcare providers. Patients play a central

role to define research priorities, contribute to thedirection of clinical queries, and gain access to

results. Another example is the Patient Reported

Outcomes Measurement Information System(PROMIS), which is funded by the US National

Institutes of Health (NIH). These measures

become the tools of scientific study to inform theeffectiveness of interventions and have already

invested in pain as a focal area. Specifically inpediatrics, this entity has made available validated

tools to assess pain interference and intensity, aswell as focusing on areas of physical function,

emotional distress, fatigue, and peer relationships.

Thus, research offers an arena not only for patientand parent participation, but also for collaboration

to define priorities for study and new forums in

which to share results.

What Do the Data Show with Regard toFamily-Centered Care?A systematic review (Shields et al. 2008)

underscored the paucity of solid quantitative

research on the effectiveness of family-centeredcare. Qualitative studies, and subsequent quanti-

tative efforts, have shown the impact of family-

centered care to (Bamm and Rosenbaum 2008;Kuo 2012):

• Improve patient outcomes

• Improve patient and family satisfaction• Improve healthcare professionals’ satisfaction

• Decrease cost

• Improve utilization of resources in health careIn line with these results, leading professional

and safety organizations have endorsed family-

centered care. In the USA, for example, theInstitute of Medicine (IOM) identified family-

centered care as one of the six attributes of

high-quality health care (IOM 1999, 2001), andthe Joint Commission incorporated a bill of rights

that included patient comfort and that active

involvement of patients and families is a strongstrategy to ensure patient safety.

Summary

The synergy between family-centered care andthe practice of pediatric pain medicine is unde-

niable. The data available assert its value to the

extent that it is sanctioned as a primary safetyand quality strategy. Yet, the challenge remains

in the translation of a philosophy in approach to

bedside practice. For some healthcare settingsthis would present a complete interdisciplinary

F 1258 Family-Centered Care

paradigm shift, while at the same time offera tremendous opportunity for culture change

in treating pain in children. It is possible.First, the system must define the professional

standards, set expectations for behavior, and

create the space for a rich partnership. Then,the system must maintain accountability to

that model, including individual practitioner

responsibility. In time, a culture will emergein which the partnership of family-centered

care will transform the experience of a child

in pain.

References

Ammentorp, J., Mainz, J., & Sabroe, S. (2005). Parents’priorities and satisfaction with acute pediatric care.Archives of Pediatric and Adolescent Medicine,159(2), 127–131.

Bamm, E. L., & Rosenbaum, P. (2008). Family-centeredtheory: Origins, development, barriers, and supports toimplementation in rehabilitation medicine. Archivesof Physical Medicine and Rehabilitation, 89(8),1618–1624.

Committee on Hospital Care. American Academy ofPediatrics & Institute for Patient- and Family-Centered Care. (2003). Family-centered care andthe pediatrician’s role. Pediatrics, 112(3 Pt 1),691–697.

Garland, L., & Kenny, G. (2006). Family nursing and themanagement of pain in children. Paediatric Nursing,18(6), 18–21.

Guerrero, A. D., et al. (2010). Racial and ethnic disparitiesin pediatric experiences of family centered care. Med-ical Care, 48(4), 388–393.

Huth, M. M., Broome, M. E., Mussatto, K. A., & Morgan,S. W. (2003). A study of the effectiveness of a painmanagement education booklet for parents of childrenhaving cardiac surgery. Pain Management Nursing,4(1), 31–39.

Institute for Family-Centered Care. Available at: www.familycenteredcare.org. Accessed 11 Apr 2012.

Institute of Medicine. (1999). To err is human: Buildinga safer health system. Washington, DC: NationalAcademies Press.

Institute of Medicine. (2001). Crossing the quality chasm:A new health system for the 21st Century. Washington,DC: National AcademiesPress.

Institute of Medicine. (2011). Relieving pain in America:A blueprint for transforming prevention, care, educa-tion, and research. Washington, DC: NationalAcademiesPress.

Kuo, D. (2012). Family-centered care: Current applica-tions and future directions in pediatric health care.Maternal and child health journal, (1092–7875),16 (2), 297.

MacKean, G. L., Thurston, W. E., & Scott, C. M. (2005).Bridging the divide between families and health pro-fessionals’ perspectives on family-centered care.Health Expectations, 8, 74–85.

Mitchell, M. J., Lemanek, K., Palermo, T. M., Crosby,L. E., Nichols, A., & Powers, S. W. (2007). Parentperspectives on pain management, coping, and familyfunctioning in pediatric sickle cell disease. ClinicalPediatrics, 46(4), 311–319.

Patient Reported Outcomes Measurement InformationSystem. Available at: www.nihpromis.org. Accessed11 Apr 2012.

Patient-Centered Outcomes Research Institute. Availableat: www.pcori.org. Accessed 11 Apr 2012.

Reid, G. J., Hebb, J. P., McGrath, P. J., Finley, G. A., &Forward, S. P. (1995). Cues parents use to assesspostoperative pain in their children. The Clinical Jour-nal of Pain, 11(3), 229–235.

Shields, L., Pratt, J., & Hunter, J. (2006). Family-centredcare: A review of qualitative studies. Journal ofClinical Nursing, 15(10), 1317–1323.

Shields, L., Pratt, J., Davis, L. M., & Hunter, J. (2008).Family-centred care for children in hospital. CochraneDatabase of Systematic Reviews, (1), CD004811.

Simons, J.,Franck,L.,&Roberson,E. (2001).Parent involve-ment in children’s pain care: Views of parents and nurses.Journal of Advanced Nursing, 36(4), 591–599.

Family-Centered Care, Approachand Basis

Definition

The American Academy of Pediatrics Committee

on Hospital Care and the Institute forFamily-Centered Care issued a joint policy state-

ment in which they defined terms as follows: “Fam-

ily-centered care is an approach to health care thatshapes health care policies, programs, facility

design, and day-to-day interactions among patients,

families, physicians, and other health care profes-sionals.” Further, “Family-centered care in pediat-

rics is based on the understanding that the family is

the child’s primary source of strength and supportand that the child’s and family’s perspectives and

information are important in clinical decision

making.”

Family-Centered Care, Approach and Basis 1259 F

F

References

American Academy of Pediatrics. (2003). Pediatrics, 112,691–696 (http://www.umassmed.edu/uploadedFiles/shriver/education/LEND/Courses/Pediatrics_FCC_and_Peds_Role_2003.pdf)

Family-Centered Care, Objective

Definition

Caredirectedat improving thehealthandwell-being

ofthefamilyanditsmembersbyassessingthefamily

health needs and identifying potential obstacles.

Cross-References

▶Chronic Pain in Children, Physical Medicine

and Rehabilitation

Family-centered Theory

▶ Family-Centered Care

FAP

▶ Familial Adenomatous Polyposis

Fascia Iliaca Compartment Block

Definition

Injection via needle or catheter of local anesthetic

deep to the fascia lata and iliaca medial to theanterior superior iliac spine and inferior to the

inguinal ligament.

Cross-References

▶Acute Pain in Children, Postoperative

Fasciculus Cuneatus

Definition

The lateral bundle of nerves in the dorsal column

referred to as the cuneate fasciculus, which ter-minates in the cuneate nucleus just off the dorsal

midline in the caudal medulla.

Cross-References

▶ Postsynaptic Dorsal Column Projection,

Anatomical Organization

Fasciculus Gracilis

Definition

The medial bundle nerves in the dorsal column

referred to as the fasciculus gracilis, which ter-minates in the gracile nucleus in the dorsal mid-

line of the caudal medulla.

Cross-References

▶ Postsynaptic Dorsal Column Projection,

Anatomical Organization

Fast-Track Surgery

▶ Postoperative Pain, Importance of

Mobilization

F 1260 Family-Centered Care, Objective

Fatigue

Definition

Fatigue is a decrement of response seen with

repeated stimulation and is a prominent attributeof nociceptors and other primary afferents.

Cross-References

▶ Pain in Humans, Electrical Stimulation (Skin,Muscle, and Viscera)

▶ Polymodal Nociceptors, Heat Transduction

FCA

▶ Freund’s Complete Adjuvant

FCA-Induced Arthritis

Definition

This is the same as CFA (Complete Freund’sAdjuvant)-induced Arthritis. An experimental

model of inducing rheumatoid arthritis byinjecting a suspension of killed mycobacteria

(Freund’s complete adjuvant, FCA) into various

tissues in rats. The classical model involves injec-tion of high doses into the tail base which pro-

duces multiple joint arthritis (polyarthritis)

accompanied by wide-spread lesions of skin andother organs. A modified method uses low-dose

local injections around a joint to produce unilat-

eral single joint arthritis.

Cross-References

▶Opioids and Inflammatory Pain

FCE

▶ Functional Capacity Evaluation

Fear and Pain

Kim Helsen1,3, Maaike Leeuw2 andJohan W. S. Vlaeyen4,5

1Research Group on Health Psychology,

KU Leuven Katholieke Universiteit Leuven,Leuven, Belgium2Department of Medical, Clinical and

Experimental Psychology, MaastrichtUniversity, Maastricht, The Netherlands3Department of Experimental–Clinical and

Health Psychology, Ghent University, Ghent,Belgium4Research Group Health Psychology, Catholic

University of Leuven, Leuven, Belgium5Department of Clinical Psychological Science,

Maastricht University, Maastricht,

The Netherlands

Synonyms

Fear of movement/(re)injury; Kinesiophobia;Pain-related anxiety; Pain-related fear

Definition

▶ Fear of pain is a general term used to describeseveral forms of fear with respect to pain.

Depending on the anticipated source of threat,

the content of fear of pain varies considerably.For example, fear of pain can be directed toward

the occurrence or continuation of pain, toward

physical activity, or toward the induction of (re)injury or physical harm. A more specific fear of

pain concerns ▶ fear of movement/(re)injury,

which is the specific fear that physicalactivity will cause (re)injury. Synonymously,

▶ kinesiophobia is defined as “an excessive,

Fear and Pain 1261 F

F

irrational, and debilitating fear of physical move-ment and activity resulting from a feeling of

vulnerability to painful injury or re-injury”(Kori et al. 1990; Lundberg et al. 2006).

Characteristics

In recent years, chronic pain has no longer beenconceptualized as purely a medical problem but

rather as a complex biopsychosocial phenome-

non in which the relationship among impair-ments, pain, and disability is weak. In chronic

pain patients, anxiety disorders frequently co-

occur, indicating that patients with persistentmusculoskeletal pain fear a variety of situations

that are not essentially related to pain

(Asmundson and Katz 2009; Asmundson et al.2004; Gatchel et al. 2007). Besides the finding

that chronic pain patients seem to suffer more

frequently from anxiety symptoms, fear and anx-iety are often an integral part of the chronic pain

problem. The experience of pain can be charac-

terized by psychophysiological (e.g., musclereactivity), cognitive (e.g., worry), and behav-

ioral (e.g., escape and avoidance) responses,

showing similarities with responses regardingfear and anxiety (Leeuw et al. 2007; Vlaeyen

and Linton 2000).

There are multiple pathways by which pain-related fear mediates disability, namely, through

escape and avoidance behaviors, through inter-

ference with cognitive functioning, throughreduced opportunities to correct the erroneous

underlying cognitions guiding the avoidance

behaviors, and through detrimental effects oflong-lasting avoidance on various physiological

systems (Crombez et al. 1999; Gheldof et al.

2006; Turk and Wilson 2010). Empirical findingssupport the notion that fear of pain is a significant

contributor to the chronification and maintenance

of chronic pain syndromes (Hirsh et al. 2008; Turkand Wilson 2010; Vlaeyen and Linton 2000).

Fear and AnxietyIn the literature describing fear of pain, the con-

cepts of fear and anxiety are often used inter-

changeably. Despite the fact that these concepts

are substantially related, some differences can bedistinguished (Asmundson et al. 2004; Leeuw

et al. 2007; Sylvers et al. 2011).Fear is the emotional expression of the fight-

flight response, which is the immediate readiness

of the body to respond to an event that is per-ceived as dangerous or threatening. Fear is there-

fore a present-oriented state that is designed to

protect the individual from the perceived imme-diate threat. ▶Anxiety, however, is a cognitive-

affective state that is rather future oriented. It

tends to occur in the anticipation of a dangerousor threatening event and is therefore more indef-

inite and uncertain in nature. Instead of initiating

the fight-flight response as in case of fear, thestate of anxiety seems to facilitate and stimulate

the fight-flight response only in case the threat-

ening event occurs. Both in fear and anxiety,cognitive, physiological, and behavioral dimen-

sions of responses can be distinguished. Physio-

logically, fear and anxiety responses arecharacterized by the activation of the sympathetic

nervous system, designed to increase the likeli-

hood of survival by promoting escape from orprotection against the perceived threat. In anxi-

ety, these physiological responses are less present

than in fear. The cognitive element, relativelymore present in anxiety, is more narrowed in

anxiety and directed in such a way that a source

of threat, when present, will be detected. Fear, onthe other hand, comprises thoughts of danger,

threat, or death, through which the attention

toward the threat is advanced, while irrelevantdistracters are ignored and the initiation of action

is stimulated. On a behavioral level, anxiety

guides motivation to engage in preventative andavoidance behaviors, while fear motivates to

engage in defensive behaviors. Despite the defi-

nition of pain-related fear, both fear and anxietyare distinct processes that contribute significantly

to chronic pain (Asmundson et al. 2004).

Hierarchy of FearBesides the important distinction between fear

and anxiety in chronic pain, understandingabout the hierarchical nature of fear and anxiety

is also an important consideration. The hierarchi-

cal structure of anxiety is displayed in Fig. 1.

F 1262 Fear and Pain

Fundamental Fears

According to the expectancy theory (Reiss and

McNally 1985), most fears can be derived fromone of three more fundamental fears or sensitiv-

ities: (1) fear of anxiety symptoms (anxiety sen-

sitivity), (2) fear of negative evaluation (socialevaluation sensitivity), and (3) fear of illness/

injury (injury/illness sensitivity). Anxiety sensi-

tivity refers to the fear of anxiety symptoms aris-ing from the belief that anxiety has harmful

somatic, psychological, and social consequences.

Social evaluation sensitivity reflects anxiety anddistress that is associated with expectations that

others will have negative evaluations about one-

self and with avoidance of evaluative situations.Finally, injury/illness sensitivity refers to fear

concerning injury, illness, or death. These funda-

mental fears are quite distinct from each otherand comprise stimuli that are considered to be

essentially aversive to most people (Asmundson

et al. 2000; Vlaeyen 2003).

Common Fears: Fear of Pain

Common fears (such as spider phobia, agorapho-bia, fear of pain) arise as the result of an interac-

tion between the fundamental fears and learning

experiences and can thus be logically derivedfrom these three fundamental fears. In contrast

to fundamental fears, they do not refer to a wide

variety of stimuli and are not essentially consid-ered to be aversive to most people. Due to fear of

anxiety, causing one to fear the symptoms that are

associated with anxiety, a common fear about

a particular situation easily arises when in the

concerning situation anxiety symptoms are

expected or likely to be experienced. In essence,anxiety sensitivity can be considered as

a vulnerability factor that exacerbates the devel-

opment and maintenance of common fears, thesame holding for injury sensitivity and social

evaluation sensitivity (Asmundson et al. 2000).

In chronic low back pain, fear of pain isa common fear that can be derived from the

fundamental fear of anxiety symptoms (anxiety

sensitivity). When someone who is highly anxi-ety sensitive expects to encounter anxiety symp-

toms during the experience of pain, fear of pain

will likely develop (Asmundson et al. 2000;Ocanez et al. 2010). However, Keogh and

Asmundson (2004) argue that it is more reason-

able to assume that fear of pain is related to injury/illness sensitivity, which is also supported by Van

Cleef et al. (2006). Fear of pain is still a relatively

general construct. Fear of pain can be directed atpain sensations as well as activities and situations

that are associated with pain. In chronic low back

pain patients, one of the more specific forms offear of pain is fear of movement/(re)injury, which

is the specific fear that physical activity will

cause (re)injury (Vlaeyen and Crombez 1999).

Specific Fears: Fear of Movement/(Re)Injury

A number of CLBP patients believe that perfor-mance of certain activities may induce or pro-

mote pain and (re)injury. Beliefs concerningharmful consequences of activities lead to fear

Trait anxiety

Anxiety Sensitivity

Traits

Fundamentalfears

Commonfears

Specificfears

Social Evaluation SensitivityInjury/lllness sensitivity

Fear of pain

Fear of movement/(re)injury

Fear and Pain, Fig. 1 Hierarchical structure of fear of pain

Fear and Pain 1263 F

F

of movement/(re)injury and consequently to theavoidance of these activities, although medical

indications for this behavioral pattern of avoid-

ance are lacking. Despite the fact that in acutepain the avoidance of daily activities may be

adaptive in facilitating healing and recovery,

avoidance behavior is no longer necessary forrecovery in chronic pain (Leeuw et al. 2007;

Vlaeyen and Linton 2000).

Cognitive Behavioral ModelsA cognitive behavioral model of chronic low

back pain has been proposed, which emphasizesthe crucial importance of the role of fear of

movement/(re)injury and avoidance behavior in

chronic low back pain patients (Vlaeyen 2003;Vlaeyen and Linton 2000). According to the

model, two opposing behavioral responses may

occur in response to acute pain: “confrontation”and “avoidance.” A gradual confrontation and

resumption of daily activities despite pain is con-

sidered as an adaptive response that eventuallyleads to the reduction of fear, the encouragement

of physical recovery, and functional rehabilita-

tion. In contrast, a catastrophic interpretation ofpain is considered to be a maladaptive response,

which initiates a vicious circle in which fear

of movement/(re)injury and the subsequentavoidance of activities augment functional

disability and the pain experience by means

of hypervigilance, depression, and disuse.Substantial support for this cognitive behavioral

model and the role of the specific fear ofmovement/(re)injury has been found (Leeuw

et al. 2007; Vlaeyen and Linton 2000).

In addition to this cognitive behavioral model,Asmundson et al. (2004) propose to update

the model by integrating the concept of anxiety

in addition to fear, referring to this as thefear-anxiety-avoidance model (Fig. 2).

This model states that catastrophizing about

pain produces fear of pain, designed to protect theindividual from the perceived immediate threat.

This fear of pain in turn might promote pain-

related anxiety. Pain-producing stimuli resultthrough pain-related fear in escape and protecting

behaviors aimed at reducing pain intensity. These

behaviors in turn strengthen erroneous beliefsabout pain, increase catastrophizing, and further

enhance pain-related fear. The addition of an

anxiety-related pathway to the pathway of pain-related fear provides a more accurate explanation

for the fact that chronic pain interferes with one’s

daily life. In the anticipation, rather than in thepresence of pain and/or injury, anxiety is evoked,

leading to an increased attention (hypervigilance)

for evidence of potential pain or injury. Thishypervigilance and psychical responses may

interact with memories and may promote mis-

interpretations of harmless stimuli as impendingdanger of pain or injury. Behaviorally, anxiety

results in avoidance and preventative behaviors,

increasing disability and disuse (Asmundsonet al. 2004).

DisuseDisability

Depression

Catastrophizing

Injury/Strain

Recovery

Exposure

Low fear

Pain experience

Avoidance

Escape

Threat perception

Hypervigilance

Painanxiety

Fearof pain

Defensive

motivation

Preventative

motivation

Arou

sal

Arou

sal

Fear and Pain,Fig. 2 Fear-anxiety-avoidance model of chronicpain (Adapted from thecognitive behavioral modelof Vlaeyen and Linton(2000) and the fear-anxiety-avoidance modelof Asmundson et al. (2004))

F 1264 Fear and Pain

Recently, the sequential relationships betweenchanges in pain catastrophizing, subsequent fear

and avoidance, and functional outcomes such asdisability or return to work were examined using

a prospective design (Wideman et al. 2009).

Although overall changes in pain catastrophizingand fear of movement were predictive for return

to work, no evidence was found that early

changes in catastrophizing were associated withlate changes in fear of movement. These findings

suggest that both components might indepen-

dently influence disability. At present, new cog-nitive behavioral models regarding pain-related

fear are evolving, focussing on behavior in con-

text. Fear of pain might result in diverse behav-iors depending on the current goal context, and

likewise, seemingly similar behaviors may be

driven by dissimilar motivational strategies(Van Damme et al. 2008; Vlaeyen et al. 2009).

Other Objects of Fear in PainMorley and Eccleston (2004) propose the exis-

tence of a range of “feared objects” in chronic

pain, because of the overwhelming threat value ofpain and three associated capacities to (1) inter-

rupt, (2) interfere, and (3) impact on one’s iden-

tity. Many potential fears arise because of theability of pain to threaten the whole range of

a person’s existence. Interruption is established

because the immediate pain experience interruptsbehavior and influences the person’s cognitive

functioning (e.g., thoughts about possible harm).

Interference is visible in the diminished accom-plishment of daily functional activities. Finally,

when repeated interference occurs to a degree

that it concerns major goals, a threat to the iden-tity is instigated. As chronic pain interferes with

current tasks, plans, and goals, the person’s per-

spective of oneself is changed, both with respectto the future and the past. Fear and anxiety are

likely to occur when the goals and the identity of

a person are threatened (Morley 2008).

Assessment of Fear of PainSeveral measurements of fear of pain are available(for an overview see McNeil and Vowles 2004).

Anxiety sensitivity can be measured by the 16-itemAnxiety Sensitivity Index (ASI) (Peterson and

Reiss 1987), measuring the degree to which peopleare concerned about the possible negative conse-

quences of anxiety symptoms. Injury/illness sensi-

tivity can be measured with the correspondingsubscale of the sensitivity index (Taylor 1993).

Fear of pain can be measured by, for example, the

Pain Anxiety Symptoms Scale (PASS)(McCracken and Dhingra 2002; McCracken et al.

1993), designed to assess pain-specific fearful

appraisals, cognitive symptoms of anxiety, physio-logical symptoms of anxiety, and escape and avoid-

ance behavior. Another way to assess pain-related

fear is by means of the Fear of Pain Questionnaire(FPQ), a self-report measure utilized in clinical as

well as in nonclinical populations (McNeil and

Rainwater 1998). Fear of movement/(re)injury canbest be measured with the 17-item Tampa Scale for

Kinesiophobia (TSK; Kori et al. 1990).

Treatment ImplicationsDue to the inextricable binding between fear and

(chronic) pain, treatment of chronic pain shouldaim to focus on these perpetuating factors. In graded

exposure in vivo, a hierarchy of fearful activities is

established, which leads to disconfirmation of painbeliefs and reduction of fear, thereby promoting

recovery of activities and functional abilities

(Vlaeyen et al. 2004; Woods and Asmundson2008). Fear- and anxiety-focused treatments seem

toprovidepromisingresults inchronic lowbackpain

patients (Bailey et al. 2010; Lohnberg 2007).

References

Asmundson,G.J.G.,&Katz, J. (2009).Understanding theco-occurrence of anxiety disorders and chronic pain: State-of-the-art.Depression and Anxiety, 26(10), 888–901.

Asmundson, G. J., Wright, K. D., & Hadjistavropoulos,H. D. (2000). Anxiety sensitivity and disabling chronichealth conditions: State of the arts and future direc-tions. Scandinavian Journal of Behaviour Therapy,29, 100–117.

Asmundson, G. J., Norton, P. J., & Vlaeyen, J. W. S.(2004). Fear-avoidance models of chronic pain: Anoverview. In G. J. G. Asmundson, J. W. S. Vlaeyen,

Fear and Pain 1265 F

F

&G. Crombez (Eds.),Understanding and treating fearof pain. Oxford: Oxford University Press.

Bailey, K. M., Carleton, R. N., Vlaeyen, J. W. S., &Asmundson, G. J. G. (2010). Treatments addressingpain-related fear and anxiety in patients with chronicmusculoskeletal pain: A preliminary review.CognitiveBehaviour Therapy, 39(1), 46–63.

Crombez, G., Vlaeyen, J. W. S., Heuts, P. H. T. G., et al.(1999). Pain-related fear is more disabling than painitself: Evidence on the role of pain-related fear inchronic back pain disability. Pain, 80, 329–339.

Gatchel, R. G., Peng, Y. B., Peters, M. L., Fuchs, P. N., &Turk, D. C. (2007). The biopsychosocial approach tochronic pain: Scientific advances and future directions.Psychological Bulletin, 133(4), 581–624.

Gheldof, E. L. M., Vinck, J., Van den Bussche, E.,Vlaeyen, J. W. S., Hidding, A., & Crombez, G.(2006). Pain and pain-related fear are associated withfunctional and social disability in an occupational set-ting: Evidence of mediation by pain-related fear. Euro-pean Journal of Pain, 10(6), 513–525.

Hirsh, A. T., George, S. Z., Bialosky, J. E., & Robinson,M. E. (2008). Fear of pain, pain catastrophizing,and acute pain perception: Relative prediction andtiming of assessment. The Journal of Pain, 9(9),806–812.

Keogh, E., & Asmundson, G. J. G. (2004). Negative affec-tivity, catastrophizing, and anxiety sensitivity. InG. J. G. Asmundson, J. W. S. Vlaeyen, & G. Crombez(Eds.), Understanding and treating fear of pain.Oxford: Oxford University Press.

Kori, S. H., Miller, R. P., & Todd, D. D. (1990).Kinesiophobia: A new view of chronic pain behavior.Pain Manage, 35–43.

Leeuw, M., Goossens, M. E. J. B., Linton, S. J., Crombez,G., Boersma, K., & Vlaeyen, J. W. S. (2007). The fear-avoidance model of musculoskeletal pain: Currentstate of scientific evidence. Journal of BehavioralMedicine, 30(1), 77–94.

Lohnberg, J. A. (2007). A review of outcome studies oncognitive behavioral therapy for reducing fear-avoidance beliefs among individuals with chronicpain. Journal of Clinical Psychology in Medical Set-tings, 14, 113–122.

Lundberg, M., Larsson, M., Ostlund, H., & Styf, J. (2006).Kinesiophobia among patients with musculoskeletalpain in primary healthcare. Journal of RehabilitationMedicine, 38, 37–43.

McCracken, L. M., & Dhingra, L. (2002). A short versionof the pain anxiety symptoms scale (PASS-20): Pre-liminary development and validity. Pain Research &Management, 7(1), 45–50.

McCracken, L. M., Zayfert, C., & Gross, R. T. (1993). Thepain anxiety symptoms scale (PASS):A multidimensional measure of pain-specific anxietysymptoms. Behavior Therapist, 16, 183–184.

McNeil, D. W., & Rainwater, A. J. (1998). Developmentof the fear of pain questionnaire-III. Journal of Behav-ioral Medicine, 21(4), 389–410.

McNeil, D. W., & Vowles, K. E. (2004). Assessment offear and anxiety associated with pain: Conceptua-lisation, methods, and measures. In G. J. G.Asmundson, J. W. S. Vlaeyen, & G. Crombez (Eds.),Understanding and treating fear of pain. Oxford:Oxford University Press.

Morley, S. (2008). Psychology of pain. British Journal ofAnaesthesia, 101(1), 25–31.

Morley, S., & Eccleston, C. (2004). The object of fearin pain. In G. J. G. Asmundson, J. W. S. Vlaeyen, &G. Crombez (Eds.),Understanding and treating fear ofpain. Oxford: Oxford University Press.

Ocanez, K. L. S., McHugh, R. K., & Otto, M. W. (2010).A meta-analytic review of the association betweenanxiety sensitivity and pain. Depression and Anxiety,27, 760–767.

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Reiss, S., & McNally, R. J. (1985). The expectancymodel of fear. In S. Reis & R. R. Bootzin (Eds.),Theoretical issues in behavior therapy. New York:Academic.

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Taylor, S. (1993). The structure of fundamental fears.Journal of Behavior Therapy and Experimental Psy-chiatry, 24, 289–299.

Turk, D. C., & Wilson, H. D. (2010). Fear of pain asa prognostic factor in chronic pain: Conceptualmodels, assessment, and treatment implications. Cur-rent Pain and Headache Reports, 14(2), 88–95.

Van Cleef, L. M. G., Peters, M. L., Roelofs, J., &Asmundson, G. J. G. (2006). Do fundamentalfears differentially contribute to pain-related fearand pain catastrophizing? An evaluation of thesensitivity index. European Journal of Pain, 10(6),527–536.

Van Damme, S., Crombez, G., & Eccleston, C. (2008).Coping with pain: A motivational perspective. Pain,139, 1–4.

Vlaeyen, J. W. S. (2003). Fear in musculoskeletal pain. InO. Dostrovsky, D. B. Carr, & M. Koltzenburg (Eds.),Proceedings of the 10th World Congress on pain,progress in pain research and management (Vol. 24,pp. 631–650). Seattle: IASP Press.

Vlaeyen, J. W. S., & Crombez, G. (1999). Fear of move-ment/(re)injury, avoidance and pain disability inchronic low back pain patients. Manual Therapy,4(4), 187–195.

Vlaeyen, J. W. S., & Linton, S. J. (2000). Fear-avoidanceand its consequences in chronic musculoskeletal pain:A state of the art. Pain, 85, 317–332.

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J. W. S. Vlaeyen, & G. Crombez (Eds.), Understand-ing and treating fear of pain (pp. 313–343). Oxford:Oxford University Press.

Vlaeyen, J. W. S., Hanssen, M., Goubert, L., Vervoort, T.,Peters, M. L., Van Breukelen, G., et al. (2009). Threatof pain influences social context effects on verbal painreport and facial expression. Behaviour Research andTherapy, 47(9), 774–782.

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Woods, M. P., & Asmundson, G. J. G. (2008). Evaluatingthe efficacy of graded in vivo exposure for the treat-ment of fear in patients with chronic back pain:A randomized controlled clinical trial. Pain, 136,271–280.

Fear Avoidance

Definition

Fear avoidance is the avoidance of activities inorder to prevent injury, reinjury, or exacerbation

of any injury or pain. It is a learned behavior to

reduce negative pain-related emotions. In thisway, pain-related fear can lead to disability,

catastrophizing beliefs, hypervigilance to bodily

signals, and avoidance behavior.

Cross-References

▶Disability, Fear of Movement

▶ Pain in the Workplace, Risk Factors forChronicity, and Psychosocial Factors

Fear Avoidance Beliefs

Definition

Fear avoidance beliefs are cognitions often foundin individuals with pain, which support avoid-

ance behavior and make participation in physical

activity programs more difficult. Patients believethat physical activity initiated their pain and that

physical activity is bound to aggravate the pain in

the long run.

Cross-References

▶Disability

▶ Fear Avoidance▶ Pain

▶ Psychological Treatment of Pain in Older

Populations

Fear of Movement/(Re)Injury

Definition

Fear related to movement and physical activity,

inextricably associated with the fear that physical

activity will cause pain and (re)injury. Fear ofmovement is most prominent in patients with

chronic pain syndromes.

Cross-References

▶Disability, Fear of Movement

▶ Fear and Pain

Fear of Pain

Definition

Pain-related fear is a general term to describe

several forms of fear with respect to pain.

Depending on the anticipated source of threat,the content of fear of pain varies considerably.

Fear of pain can be directed toward the occur-rence or continuation of pain, toward physical

activity, or toward the induction of (re)injury or

physical harm.

Cross-References

▶Disability, Fear of Movement

▶ Fear and Pain▶Muscle Pain, Fear-Avoidance Model

Fear of Pain 1267 F

F

Fear Reduction Through ExposureIn Vivo

Jeroen R. De Jong1 and Johan W. S. Vlaeyen2,3

1Department of Rehabilitation, University

Hospital Maastricht, Maastricht,The Netherlands2Research Group Health Psychology, Catholic

University of Leuven, Leuven, Belgium3Department of Clinical Psychological Science,

Maastricht University, Maastricht,

The Netherlands

Synonyms

Exposure in vivo; Exposure treatment; Extinc-

tion; Graded exposure; Graded exposure in vivowith behavioral experiments

Definition

Exposure in vivo, originally based on ▶ extinc-tion of ▶ Pavlovian conditioning (Bouton 1988),

is currently viewed as a cognitive process during

which fear is activated and catastrophic expecta-tions are being challenged and disconfirmed,

resulting in reduction of the threat value of theoriginally fearful stimuli. During graded expo-

sure, special attention goes to the establishment

of an individual hierarchy of the ▶ pain-relatedfear stimuli. Exposure in vivo includes activities

that are selected based on the fear hierarchy and

the idiosyncratic aspects of the fear stimuli.

Characteristics

Inorder toproducedisconfirmationsbetweenexpec-

tations of pain and harm, the actual pain, and theother consequences of the activity or movement,

Philips (1987) was one of the first to argue for

repeated, graded, and controlled exposures to suchsituations. Experimental support for this idea is pro-

vided by the match-mismatch model of pain

(RachmanandArntz 1991),which states that people

initially tend tooverpredict howmuchpain theywillexperience, but after some exposures these predic-

tions tend to be corrected to match with the actualexperience.Crombez et al. (2002) andGoubert et al.

(2002) found a similar pattern in a sample of chronic

low back pain patients, who were requested toperform certain physical activities. As predicted,

the chronic low back pain patients initially

overpredicted pain, but after repetition of the activ-ity, the overprediction was readily corrected.

Overpredictions of pain and the negative

consequences of pain are more pronounced in indi-viduals reporting increasedfearofpain.Anumberof

studies examined the effectiveness of a graded

▶ exposure in vivo treatment in reducing pain-related fear, ▶pain catastrophizing, and pain dis-

ability in chronic pain patients who were referred

for outpatient behavioral rehabilitation (Vlaeyenet al. 2002a, b, c; Vlaeyen et al. 2001; de Jong

et al. 2005a, b, 2008, 2012; Leeuw et al. 2008;

Linton et al. 2008; Woods and Asmundson 2008).Theses showed improvements in pain-related fear,

pain catastrophizing, and pain disability whenever

the graded exposure was initiated. Measured withambulatory activity monitors, the improvements

also generalized to increases in physical activity

in the home situation (Vlaeyen et al. 2002a).Besides behavioral and cognitive changes, one

study in patients with ▶Complex Regional Pain

Syndrome (CRPS) even found observed positivechanges in edema, skin color, excessive sweating,

and motor function disturbances (de Jong et al.

2005a). It seems that graded exposure to painfulactivities, movements, and/or situations that were

previously avoided may indeed be a successful

treatment approach for pain patients reportingsubstantial pain-related fear.

Graded Exposure In VivoWe suggest that the intervention generally be

designed in three steps: cognitive-behavioral

assessment, education, and exposure in vivowith ▶ behavioral experiments.

Cognitive-Behavioral AssessmentSpecific Questionnaires A basic question that

may be asked is as follows: “What is the nature of

the perceived threat?” The answer is not as simple

F 1268 Fear Reduction Through Exposure In Vivo

as it seems. Patients may not view their problem asinvolving fear at all and may simply see inability in

performing certain activities due to pain. In addi-tion, the specific nature of pain-related fear varies

considerably, making an idiosyncratic approach

almost indispensable. Patients may not fear painitself, but the impending (re)injury it signals: pain

is seen as a warning signal for a seriously threaten-

ing situation. The list below outlines pain-relatedfear questionnaires, including sample items:

Pain and Impairment Relationship Scale(PAIRS: Riley et al. 1988)

“I have to be careful not to do anything that

might make my pain worse.”

“All of my problems would be solved if mypain would go away.”

Survey of Pain Attitudes (SOPA [SubscaleHarm]: Jensen et al., 1992)

Measures of Pain Catastrophizing

Pain Catastrophizing Scale (PCS: Sullivan

et al. 1995)Rumination: “I keep thinking about howmuch

it hurt.”

Amplification: “I grow afraid that the pain willget worse.”

Helplessness: “There’s nothing I can do to

reduce the intensity of the pain.”Pain Cognition List (PCL [Subscale

catastrophizing]: VanBreukelen andVlaeyen 2005)Cognitive Error Questionnaire (Lefebvre 1981)Vignettes about catastrophizing, overgenera-

lization, personalization, and selective abstrac-

tion: e.g., “You have a painful back problem buthave continued to work. Although you got quite

a bit done today, you quit work a little early

because your back was really hurting. You thinkto yourself, ‘What a terrible day, it seems like

I can’t get anything done’.”

Coping Strategies Questionnaire (CSQ[Subscale catastrophizing]: Rosenstiel and

Keefe 1983)

“I feel I can’t stand it anymore.”Pain-Related Fear and Anxiety

Tampa Scale for Kinesiophobia (TSK: Miller

et al. 1991)Harm:

“My body is telling me I have something dan-

gerously wrong.”

Avoidance of activity:“Pain lets me know to stop exercising so that

I don’t injure myself.”Pain Anxiety Symptoms Scale (PASS:

McCracken et al. 1992)

Cognitive anxiety:“I can’t think straight when in pain.”

Escape/avoidance:

“I will stop any activity as soon as I sense paincoming on.”

Fear:

“When I feel pain, I am afraid that somethingterrible will happen.”

Physiological anxiety:

“I begin trembling when engaged in anactivity that increases pain.”

Fear-Avoidance Beliefs Questionnaire(FABQ: Waddell et al. 1993)

Fear-avoidance beliefs about work:

“My work might harm my back.”

Fear-avoidance beliefs about physicalactivity:

“My pain was caused by physical activity.”

Interview The semi structured interview is an

additional tool to better estimate the role of pain-

related fear in the pain problem. It includes infor-mation about the antecedents (situational and/or

internal), catastrophic (mis)interpretations, and

consequences of the pain-related fear. Informationis gathered about the assumptions patients make of

the association between activities, pain, and (re)

injury. Factors that often seem to be associatedwith the development of fear are the characteristics

of pain onset and the ambiguity surrounding the

presence or absence of positive findings onmedico-diagnostics. Reports about misconceptions and

misinterpretations of information can later be used

during the educational part of the intervention.Finally, the interview should also clarify whether

other problems such as major depression, marital

conflicts, or disability claims warrant specific atten-tion before or after treatment.

Graded Hierarchies What is the patient actu-ally afraid of? In addition to checklists of daily

activities, the presentation of visual materials,

such as pictures of stressing activities and

Fear Reduction Through Exposure In Vivo 1269 F

F

movements reflecting the full range of situationsavoided by the patient, can be quite helpful in the

development of graded hierarchies. They startwith activities or situations that provoke only

mild discomfort and end with those that are

beyond the patient’s present abilities. The Photo-graph Series of Daily Activities uses photographs

representing various physical daily activities to

be placed along a fear thermometer (Dubberset al. 2003; Jelinek et al. 2003; Kugler et al.

1999; Leeuw et al. 2007).

Behavioral Tests Sometimes, patients find it

hard to really estimate the harmfulness of an

activity when it has been avoided extensively.For cases in which even pictorial methods

(PHODA) do not work, behavioral tests can be

introduced. These consist of performing anactivity that has been avoided previously, while

performance indices (e.g., time, distance, number

of repetitions) are measured. Target behaviorscan be derived from PHODA items, and in most

cases the behavioral tests can be considered as

a variant of the exercise tolerance test describedby Fordyce (Fordyce 1976).

EducationOne of themajor goals of the educational section is

to increase the willingness of patients to finally

engage in activities they avoided for a long time.The aim is to correct the misinterpretations and

misconceptions that occurred early on during the

development of the pain-related fear. The educa-tional section is more than just reassuring that there

are no specific physical abnormalities. Unambigu-

ously educating the patient in a way that the patientviews his or her pain as a common condition that

can be self-managed, rather than a serious disease

or condition that needs careful protection, isa useful first step. It can be explained to patients

that they may have probably overestimated the

value of diagnostic tests and that in symptom-freepeople similar abnormalities can also be found.

Graded Exposure In Vivo with BehavioralExperiments

Graded Exposure In Vivo As firsthand

evidence of actually experiencing oneselves

behaving differently is far more convincing thanrational argument, the most essential step

consists of graded exposure to the situations thefearful patient has identified as “dangerous” or

“threatening.” The patient is encouraged to

engage in these fearful activities as much aspossible, until disconfirmation has occurred and

anxiety levels have decreased. If the rating has

decreased significantly, the therapist mayconsider moving on to the next item of the hier-

archy. Each activity or movement is first modeled

by the therapist. His presence, initially acting asa safety signal to promote more exposures, is

gradually withdrawn to facilitate independence

and to create contexts that mimic those of thehome situation (Vlaeyen et al. 2012).

Behavioral Experiments The graded exposureto fear-eliciting activities can be carried out in the

form of a behavioral experiment in which

a collaborative empiricism is the bottom line.The essence of a behavioral experiment is that

the patient performs an activity to challenge the

validity of his catastrophic assumptions andmisinterpretations. These assumptions take the

form of “If . . . then . . .” statements and are

empirically tested in such a behavioralexperiment.

Generalization and Maintenance of ChangeExposure to physical activities is not likely to

result in a fundamental change in the belief of

the pain patient that certain movements areharmful or painful (Goubert et al. 2002). More

likely, the patient will learn that the movements

involved in the exposure treatment are lessharmful or painful than anticipated. In other

words, during successful exposure, exceptions

to the rule are learned, rather than there beinga fundamental change of that rule. Generaliza-

tion and maintenance can be enhanced by the

following measures. First, exposure to the fullspectrum of contexts and natural settings in

which fear has been experienced is required.

Second, during the exposure, it is best that stim-uli be varied as much as possible. Third,

expanded-spaced, rather than a massed expo-

sure, is preferred (Vlaeyen et al. 2012).

F 1270 Fear Reduction Through Exposure In Vivo

References

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Crombez, G., Eccleston, C., Vlaeyen, J. W.,Vansteenwegen, D., Lysens, R., & Eelen, P. (2002).Exposure to physical movements in low back painpatients: Restricted effects of generalization. HealthPsychology, 21, 573–578.

de Jong, J. R., Vlaeyen, J.W. S., Onghena, P., Cuypers, C.,den Hollander, M., & Ruygrok, J. (2005a). Reductionof pain-related fear in complex regional pain syndrometype I: The application of graded exposure in vivo.Pain, 116, 264–275.

de Jong, J. R., Vlaeyen, J. W., Onghena, P., Goossens,M. E., Geilen, M., & Mulder, M. (2005b). Fear ofmovement/(Re) injury in chronic low back pain: Edu-cation or exposure In Vivo as mediator to fear reduc-tion? The Clinical Journal of Pain, 21, 9–17.

de Jong, J. R., Vangronsveld, K., Peters, M. L., Goossens,M. E., Onghena, P., Bulte, I., et al. (2008). Reductionof pain-related fear and disability in post-traumaticneck pain: A replicated single-case experimentalstudy of exposure in vivo. The Journal of Pain,9(12), 1123–1134.

de Jong, J. R., Vlaeyen, J. W. S., van Eijsden, M., Loo, C.,& Onghena, P. (2012). Reduction of pain-related fearand increased function and participation in work-related upper extremity pain (WRUEP): Effects ofexposure in vivo. Pain, 10, 2109–2118.

Dubbers,A.T.,Vikstrom,M.H.,&DeJong, J.R. (2003).ThePhotographseriesofDailyActivities (PHODA):Cervicalspine and shoulder [CD-ROM version 1.2]. The Nether-lands:HogeschoolZuyd,UniversityMaastricht and Insti-tute for Rehabilitation Research (iRv).

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Leeuw, M., Goossens, M. E. J. B., van Breukelen, G.,Boersma, K., & Vlaeyen, J. W. S. (2007). Measuringperceived harmfulness of physical activities in patientswith chronic low back pain: The photograph series ofdaily activities [Short electronic version]. The Journalof Pain, 8, 840–849.

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Fear-Anxiety-Avoidance Model

Definition

The Fear-Anxiety-Avoidance Model states that

catastrophic misinterpretations in response toacute pain can lead to fear of pain and subse-

quently to pain-related anxiety. Fear urges the

escape from the pain stimulus, while anxietyin anticipation of pain or threat urges avoidance

of those situations. As a result of this, a

self-perpetuating cycle develops in whichsubsequent avoidance of activities augments

functional disability and the pain experience

by means of hypervigilance, depression, anddecreased physical fitness, thereby further

advancing chronicity.

Cross-References

▶ Fear and Pain

Fear-Avoidance

▶Disability, Fear of Movement

Fear-Avoidance Model

Definition

The basic tenet of the fear-avoidance model is

that catastrophic misinterpretations in response toacute pain lead to pain-related fear, which subse-

quently urges the escape from the painful stimuli,

and to selectively attend to bodily sensations. Asa result, a self-perpetuating cycle develops in

which subsequent avoidance of activities aug-

ments functional disability, depression, anddecreased physical fitness.

Cross-References

▶ Fear Reduction through Exposure in Vivo▶Muscle Pain, Fear-Avoidance Model

Feasible

Definition

The simple, economic, and easy application of

a measure

Cross-References

▶ Pain Assessment in Neonates

Feedback Control of Pain

Definition

Ascending nociceptive signals activate supra-

spinal mechanisms (e.g., an inhibitory brainstem-spinal pathway) that suppress spinal/trigeminal

nociceptive transmission.

F 1272 Fear-Anxiety-Avoidance Model

Cross-References

▶Descending Modulation and Persistent Pain

Fee-for-Service

Definition

Patients or insurance pay for medical care as it is

needed and according to the service provided.

Cross-References

▶Disability Management in Managed Care

System

Female Reproductive Organ PainModel

▶Visceral Pain Models, Female Reproductive

Organ Pain

Female Sex Steroid Hormonesand Pain

Jennifer Brawn1 and Katy Vincent2

1P.A.I.N. Group, Center for Pain and the Brain,

Boston Children’s Hospital, Harvard MedicalSchool, Waltham, MA, USA2Nuffield Department of Obstetrics and

Gynaecology, The Women’s Centre, JohnRadcliffe Hospital, University of Oxford,

Oxford, UK

Introduction

It widely understood that females are dispropor-

tionately affected by pain syndromes whencompared to their male counterparts. This clinical

skew is notable in conditions such as migraine

headache, temporomandibular joint disorder(TMJD), irritable bowel syndrome (IBS), and

fibromyalgia (Unruh 1996). In addition to thehigher prevalence of females with pain condi-

tions, there have been reports of cyclical patterns

of pain onset and severity (Martin 2009). Thisdisparity in pain experience has resulted in

a significant body of research comparing

gender-specific physiological differences. Mostexperimental pain studies suggest that females

are more sensitive to pain than males, although

there are inconsistencies in the literature (Martin2009; Fillingim et al. 2009). Consequently,

researchers have focused on female biology, spe-

cifically the menstrual cycle, to untangle thisimportant clinical and biological conundrum.

The two main female sex steroid hormones, pro-

gesterone and estradiol, are thought to influencepain processing through alteration of a variety of

neural mechanisms.

Characteristics

Pain Perception in Healthy Females over theMenstrual CycleAnimal models have allowed for improvedmechanistic understanding of the central effects

of progesterone and estradiol; however, differ-

ences in the physiology of the ovarian cyclebetween species causes difficulty in extrapolating

some of these findings to humans. In rodents,

these hormones have been implicated ina variety of pain-related pathways including the

gamma-aminobutyric acid (GABA), glutamate,

opioid, and dopamine systems. Thus, estradiolappears to mediate inflammatory responses,

increase opioidergic tone, and promote reuptake

of glutamate, while progesterone is thought toalter GABAergic inhibitory activity by increas-

ing binding affinity through its metabolite

allopregnanolone. Certainly, in rodents there isa notable cyclical trend toward greater pain

sensitivity in the proestrus phase, a time that is

characterized by dramatic fluctuations of proges-terone and estradiol. However, researchers

have also observed increased sensitivity at other

Female Sex Steroid Hormones and Pain 1273 F

F

points including estrus, metestrus, and diestrus(Reviewed in Martin 2009). In humans, results

are more difficult to interpret. A number of fac-tors contribute to this problem, not least the dif-

ferent definitions and methods of verification of

the menstrual cycle phases (Sherman andLeResche 2006).

Evaluating Menstrual Cycle Changes in PainPerceptionIn a meta-analysis performed by Riley et al.

1999, 16 studies were categorized by stimuliand assessed (Fillingim et al. 2009). For the

cold pressor test, pressure, heat, and ischemic

pain, sensitivity was lowest in the follicularphase, characterized by low hormone levels

with estradiol increasing in the latter half. Elec-

trical pain sensitivity, however, was lowest in theluteal and highest in the periovulatory phases.

Only one of the included studies obtained hor-

monal measures. In a subsequent methodologicalreview, researchers were skeptical of this analysis.

They found inconsistent cyclical patterns in

thermal, mechanical, and ischemic pain percep-tion. The only notable pattern involved electrical

pain with studies reporting decreased sensitivity in

the early luteal phase (Sherman and LeResche2006).

In a recent narrative review of cyclical pain

response in healthy females, Martin 2009 ana-lyzed the results of 19 human studies. To make

findings comparable, the author redefined the

reported cycle phases based on the actual testdates. Observed trends were summarized using

three categories. The author noted that six studies

reported no cyclical changes in pain sensitivity.However, five studies observed that pain sensi-

tivity increased in phases characterized by fluc-

tuating estradiol and increasing progesterone(late follicular and early luteal). Seven studies

found that pain sensitivity increased in phases

characterized by low or decreasing estradiol andprogesterone (late luteal or early follicular). It

should be noted that only four of the studies

analyzed had blood progesterone and estradiollevels to verify menstrual cycle phase. An addi-

tional three studies confirmed ovulation through

biological measures.

Hormonal Measures and Pain PerceptionHormonal assays are key to untangling the

complex relationship between progesterone, estra-

diol, and pain. While countless studies have eval-uated changes in pain perception over the

menstrual cycle, only a small number have

obtained either plasma or serum hormone levels.These measures allow for analysis of pain changes

independent of experimental sessions or some-

what arbitrary divisions of the menstrual cycle(Sherman and LeResche 2006). Fillingim et al.

1997 conducted the first study that used blood-

derived estrogen and progesterone levels to eval-uate changes in pain sensitivity, specifically pain

onset and threshold, over the menstrual cycle.

A significant correlation was observed betweenelevated plasma estrogen levels and low thermal

pain onset and threshold measures. In a study that

examined diffuse noxious inhibitory control(DNIC), within the ovulatory phase, pain-induced

analgesia was positively correlated with progester-

one levels (Tousignant-LaFlamme and Marchand2009). Ring et al. 2009 observed that within the

luteal phase, progesterone, estradiol, and pain

ratings from needle and catheter insertion werepositively correlated. While Stening et al. 2007

used the cold pressor test to measure transition

from mild to moderate pain (activation time) andnoted that shorter activation times were signifi-

cantly correlated with high progesterone levels;as were maximal pain ratings. Estradiol, however,

was not significantly correlated with any of the

results. Stening and colleagues (2007) alsoanalyzed the combined impact of estradiol and

progesterone on pain perception. When present

together at high levels, estradiol and progesteroneappeared to decrease pain sensitivity, with

estradiol mediating progesterone’s apparent

pronociceptive influence. Alternatively, severalstudies have not observed any correlations

between hormone levels and pain measures

(Craft 2007; Klatzkin et al. 2010; Kowalczyket al. 2006).

Menstrual Cycle DisordersDue to their close correlation with hormonal

changes, several pain studies have evaluated

females with cyclical medical conditions.

F 1274 Female Sex Steroid Hormones and Pain

However, a major difficulty with this strategy isdisentangling hormonal influences on pain per-

ception per se from influences on the pathologycausing the symptoms. Dysmenorrhea is

a menstrual cycle condition characterized by

extreme abdominal and back pain during menses.It has been speculated that low or decreasing

progesterone levels may trigger dysmenorrheic

symptoms (Martin 2009). In a clinical study,Granot et al. 2001 compared heat and laser pain

thresholds in dysmenorrheic women and healthy

females over four experimental sessions.Dysmenorrheic women were more sensitive to

pain from both stimuli. For the laser stimuli, both

groups appeared to have the lowest pain sensitivityin the luteal phase (high plasma progesterone and

estradiol) and the highest during the follicular

phase (increasing plasma estradiol). Cycle phase,however, did not affect dysmenorrheic women’s

response to the heat stimuli. Similarly, Vincent

and colleagues (2011) demonstrated increasedsensitivity to noxious heat in dysmenorrheic

women compared to pain-free controls, but found

no influence of cycle phase in either group. In thisstudy, the timing of the three experimental

sessions was chosen to maximize endogenous

variation in levels of estradiol and progesterone.Premenstrual dysphoric disorder (PMDD) is

a luteal phase condition characterized by extreme

physical and emotional changes. While theunderlying pathology of the condition remains

unclear, it has been postulated that women with

PMDD may have abnormal levels of sex steroidhormones and/or altered neurotransmitter regula-

tion by these hormones. In support of this, two

studies have shown luteal phase estradiol andprogesterone levels to be higher in women with

PMDD than controls (Straneva et al. 2002;

Epperson et al. 2002). Interestingly, althoughthere was no difference in cortical GABA levels

between the groups, GABA levels decreased

across the cycle in healthy women but increasedin those with PMDD, with the steroid hormones

appearing to exert opposing effects in the two

groups (e.g., a positive correlation betweenGABA and both estradiol and progesterone in

the women with PMDD and a negative correla-

tion in the control women) (Epperson et al. 2002).

PMDD sufferers demonstrated higher pain andunpleasantness ratings in response to noxious

stimuli in the luteal compared to the follicularphase, and significantly lower pain tolerance

and threshold measures than healthy controls in

all menstrual cycle phases (Straneva et al. 2002).

Chronic Pain Conditions and HormonalTreatmentGiven the prevalence of pain conditions in the

female population, studies have focused on both

evaluating differences in experimental painresponse and deconstructing patterns of increased

pain. Chronic pain conditions such as fibromyal-

gia, temporomandibular joint disorder (TMJD),and migraine appear to worsen at times of low or

rapidly decreasing estradiol (LeResche et al.

2003), while symptoms from IBS, interstitialcystitis/painful bladder syndrome, and migraine

as well as a variety of gynecological pain

conditions can be improved by pharmacologicalmanipulation of hormonal status (Mathias et al.

1994; Lentz et al. 2002; Silberstein and Goldberg

2007). Once again, effects of hormones on theunderlying pathologies cannot be excluded;

however, Sherman et al. 2005 did find that

females with TMJD were more sensitiveto experimental pain during the mid-luteal and

menstrual phases.

Neuroimaging StudiesNeuroimaging technology has added an interest-

ing dimension to the field (reviewed by Vincentand Tracey 2010). Studies of pain perception in

healthy subjects suggest alterations in the cere-

bral response to noxious stimuli in differinghormonal states, although the findings from

individual studies are not entirely consistent

(Choi et al. 2006; de Leeuw et al. 2006). Unfor-tunately, to date, no studies have used

neuroimaging techniques to investigate the

relationship between steroid hormones and thecerebral response to pain in patients with

a chronic pain condition. However, studies in

healthy subjects further strengthen the evidencefor interactions between sex hormones and

endogenous pain modulatory systems; most strik-

ingly for estradiol and the mu-opioid system

Female Sex Steroid Hormones and Pain 1275 F

F

(Smith et al. 2006), but also with GABA asdiscussed earlier and potentially other systems

including the descending pain inhibitory system.

Summary

ConclusionDespite the sheer number of studies, much workis needed to develop a cohesive understanding of

individual and combined effects of estradiol and

progesterone on pain perception. As noted bymany reviews, reproducible, standardized meth-

odologies are greatly needed (Martin 2009;

Sherman and LeResche 2006; Riley et al. 1999).The field of pain and hormones is complex, thus it

is important to minimize as much research varia-

tion as possible.

References

Choi, J. C., Park, S. K., Kim, Y. H., Shin, Y. W.,Kwon, J. S., Kim, J. S., et al. (2006). Different brainactivation patterns to pain and pain-related unpleasant-ness during the menstrual cycle. Anesthesiology,105(1), 120–127.

Craft, R. M. (2007). Modulation of pain by estrogens.Pain, 132(Suppl. 1), S3–S12.

de Leeuw, R., Albuquerque, R. J., Andersen, A. H., &Carlson, C. R. (2006). Influence of estrogen on brainactivation during stimulation with painful heat.Journal of Oral and Maxillofacial Surgery: OfficialJournal of the American Association of Oral andMaxillofacial Surgeons, 64(2), 158–166.

Epperson, C. N., Haga, K., et al. (2002). Cortical gamma-aminobutyric acid levels across the menstrual cycle inhealthy women and those with premenstrual dysphoricdisorder: a proton magnetic resonance spectroscopystudy. Archives of General Psychiatry, 59(9), 851–858.

Fillingim, R. B., Maixner, W., Girdler, S. S., Light, K. C.,Harris, M. B., Sheps, D. S., et al. (1997). Ischemic butnot thermal pain sensitivity varies across the menstrualcycle. Psychosomatic Medicine, 59(5), 512–520.

Fillingim, R. B., King, C. D., Ribeiro-Dasilva, M. C.,Rahim-Williams, B., & III Riley, J. L. (2009). Sex,gender, and pain: A review of recent clinical and exper-imental findings. The Journal of Pain, 10(5), 447–485.

Granot,M.,Yarnitsky,D., Itskovitz-Eldor, J.,Granovsky,Y.,Peer, E., & Zimmer, E. Z. (2001). Pain perception inwomen with dysmenorrhea. Obstetrics andGynecology, 98(3), 407–411.

Klatzkin, R. R., Mechlin, B., & Girdler, S. S. (2010).Menstrual cycle phase does not influence gender

differences in experimental pain sensitivity. EuropeanJournal of Pain, 14(1), 77–82.

Kowalczyk, W. J., Evans, S. M., Bisaga, A. M.,Sullivan, M. A., & Comer, S. D. (2006). Sex differ-ences and hormonal influences on response to coldpressor pain in humans. The Journal of Pain: OfficialJournal of the American Pain Society, 7(3), 151–160.

Lentz, G. M., Bavendam, T., Stenchever, M. A.,Miller, J. L., & Smalldridge, J. (2002). Hormonalmanipulation in women with chronic, cyclic irritablebladder symptoms and pelvic pain. American Journalof Obstetrics and Gynecology, 186(6), 1268–1271;discussion 1271–1263.

LeResche, L., Mancl, L., Sherman, J. J., Gandara, B., &Dworkin, S. F. (2003). Changes in temporomandibularpain and other symptoms across the menstrual cycle.Pain, 106(3), 253–261.

Martin, V. T. (2009). Ovarian hormones andpain response: A review of clinical and basic sciencestudies. Gender Medicine, 6(Suppl. 2), 168–192.

Mathias, J. R., Clench, M. H., Roberts, P. H., &Reeves-Darby, V. G. (1994). Effect of leuprolideacetate in patients with functional bowel disease.Long-term follow-up after double-blind, placebo-controlled study. Digestive Diseases and Sciences,39(6), 1163–1170.

Riley, J. L., 3rd, Robinson,M. E.,Wise, E. A., & Price, D. D.(1999). Ameta-analytic review of pain perception acrossthe menstrual cycle. Pain, 81(3), 225–235.

Ring, C., Veldhuijzen van Zanten, J. J., & Kavussanu, M.(2009). Effects of sex, phase of the menstrual cycleand gonadal hormones on pain in healthy humans.Biological Psychology, 81(3), 189–191.

Sherman, J. J., & LeResche, L. (2006). Does experimentalpain response vary across the menstrual cycle?A methodological review. American Journal ofPhysiology. Regulatory, Integrative and ComparativePhysiology, 291(2), R245–R256. doi:10.1152/ajpregu.00920.2005.

Sherman, J. J., LeResche, L., Mancl, L. A., Huggins, K.,Sage, J. C., & Dworkin, S. F. (2005). Cyclic effects onexperimental pain response in women with temporo-mandibular disorders. Journal of Orofacial Pain,19(2), 133–143.

Silberstein, S. D., & Goldberg, J. (2007). Menstruallyrelated migraine: Breaking the cycle in your clinicalpractice. The Journal of Reproductive Medicine,52(10), 888–895.

Smith, Y. R., Stohler, C. S., Nichols, T. E., Bueller, J. A.,Koeppe, R. A., & Zubieta, J. K. (2006). Pronociceptiveand antinociceptive effects of estradiol through endog-enous opioid neurotransmission in women.The Journal of Neuroscience: The Official Journal ofthe Society for Neuroscience, 26(21), 5777–5785.

Stening, K., Eriksson, O., Wahren, L., Berg, G.,Hammar, M., & Blomqvist, A. (2007). Pain sensationsto the cold pressor test in normally menstruatingwomen: Comparison with men and relation to men-strual phase and serum sex steroid levels. American

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Straneva, P. A., Maixner, W., Light, K. C., Pedersen, C. A.,Costello, N. L., & Girdler, S. S. (2002). Menstrualcycle, beta-endorphins, and pain sensitivity in premen-strual dysphoric disorder. Health Psychology: OfficialJournal of theDivision of Health Psychology, AmericanPsychological Association, 21(4), 358–367.

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Femoral Nerve Block

Definition

Local anesthetic blockade of the femoral nervethat provides sensory innervation to the upper

leg. It provides prompt analgesia and muscle

relaxation in children with femoral shaft fractures.

Cross-References

▶Acute Pain in Children, Postoperative

Fentanyl

Definition

Fentanyl is a synthetic opioid that is

a phenylpiperidine derivative and structurally

related to meperidine.

Cross-References

▶ Postoperative Pain, Fentanyl

Fetal Pain During Prenatal Surgery

Carlo Valerio BellieniNeonatal Intensive Care Unit, University

Hospital, Siena, Italy

Introduction

The main argument in favor of fetal in utero

analgesic treatment is that fetuses prematurely

born are commonly entitled to receive routineanalgesia, because newborns’ pain is a widely

accepted fact. This is substantiated by observa-

tional studies, and by the anatomical develop-ment of the pain system, that is increasingly

mature with age, in prematurely born fetuses.

Thus, if a premature is entitled to analgesia, thesame should be due to a fetus with the same level

of development.

Conversely, those arguing against fetalanalgesic treatment say that until a certain fetal

age, the absence of a cortico-thalamic link is an

absolute obstacle to awareness and to pain sensa-tion. Moreover, they affirm that the fetus is in

a continuous state of sleep, with almost absence

of awakeness that cannot be evocated neitherby external stimuli, and therefore, it is in

a continuous state of endogenous sedation.Here, we will analyze three main data:

(a) the development of pain pathways in the

fetus; (b) fetus’ behavior; (c) fetal analgesia.

Definition

Fetal surgery has recently made rapid progresses

(Wilson et al. 2010). Now it is possible to treatsome mechanical anomalies before birth, and this

in some cases has brought clear advantages to the

babies, who have not to wait birth to be cured. Forinstance, fetal surgery is used in fetuses with con-

genital diaphragmatic hernia, inwhom lung growth

is triggered by percutaneous tracheal occlusion. Itcan also be used to treat urinary obstructions.Many

fetal interventions remain investigational, but ran-

domized trials have established the role of in utero

Fetal Pain During Prenatal Surgery 1277 F

F

surgery for a number of conditions, making fetalsurgery a clinical reality. The safety of fetal surgery

is such that even nonlethal conditions, such asmyelomeningocele repair, can be considered an

indication. This leads to consider the opportunity

of providing analgesia and anesthesia to the fetus.Of course, we have to wonder if a concern about

fetal pain is justified, and this means to have an

evidence-based opinion about the possibility forthe fetus to feel pain.

Characteristics

Development of Pain PathwaysAnatomical and functional perception of pain

develops throughout the gestational process.

Peripheral receptors develop very early and maybe seen by the ninth week of gestational age (GA)

and are abundant by the 22nd week GA (Lowery

et al. 2007). Four or five weeks after fertilization,pain receptors appear around the mouth, followed

by nerve fibers, which carry stimuli to the brain.

By 18 weeks GA, pain receptors have appearedthroughout the body (Blackburn 2003). Connec-

tions between peripheral receptors and afferent

fibers ending in the dorsal horn start as early as8 weeks GA and the myelination of these fibers

continues during development. Starting at 10–13

weeks GA, the afferent system located in thesubstantia gelatinosa of the spinal cord’s dorsal

horn is developing. Connections to the thalamus

begin at 14 weeks and are completed by 20 weeksGA, and thalamocortical connections or are pre-

sent from 20 weeks GA, and are more developed

by 26–30 weeks (Kostovic and Goldman-Rakic1983). The neurons of the cerebral cortex begin

a migration from the periventricular zone at

8 weeks gestation, and by 24–30 weeks GA, thecortex has acquired a full complement of neurons

(Rodeck and Whittle 2008). Electroencephalo-

graphic activity appears for the first time at 20weeks, becomes synchronized at 26 weeks GA,

and reveals wake-sleep cycles at 30 weeks GA.

It is possible to measure evoked potentials fromthe cortex from 24 weeks GA, with an objective

evidence that a peripheral stimulus can cause

cortical activation (Wilken and Gortner 2000).

An increase in stress hormones happens dur-ing fetal potentially painful transfusions: Piercing

the fetal abdomen to access the intrahepatic vein(IHV) for transfusion is associated with substan-

tial rises in these hormones from as early as 18

weeks GA. The median increase in beta-endorphin levels was 590 %, in cortisol levels

was 183 %, and median increase in noradrenaline

levels was 196 % (Giannakoulopoulos et al.1994, Giannakoulopoulos et al. 1999).

It has been hypothesized that during surgery,

despite general analgesia with opioids, metabolicchanges due to pain might be present, indicating

a production of stress hormones independent of

consciousness, (Fitzgerald et al. 2003) but severalstudies show that analgesia inhibits both con-

sciousness and the production of stress hormones

(Desborough 2000), thus, this increase seems dueto actual stress.

Clinical evidence for perception mediated by

subcortical centers comes from infants and childrenwith hydranencephaly (Marın-Padilla 1997;

Takada et al. 1989). Despite total or near-total

absence of the cortex, these children clearly possessdiscriminative awareness. They seem to distinguish

familiar from unfamiliar people and environments

and are capable of some social interaction, visualorienting, musical preferences, appropriate affec-

tive responses, and associative learning (Shewmon

et al. 1999). Recent studies highlight the possibilityof a subcortical form of consciousness, that has

been recently evidenced by several authors in

adult healthy patients (Denton et al. 2009; Merker2007; Johnson 2005; Ohman et al. 2007).

Fetal Behavioral StatesFetuses spend most gestational time in sleep:

Nevertheless term fetuses spend 9 % of their

daytime in a wake state (Pillai and James 1990).Some argue that this continuous sleep state is

induced by warmth and adenosine in the blood,

but fetal adenosine levels (Yoneyama et al. 1996)are not distinct from mothers’ (Yoneyama et al.

2000), in whom it does not induce sleep or anal-

gesia. Vibroacoustical stimulation, though littleabove the background noise, within the womb

can induce awakening in fetuses (Leader and

Fifer 1995). More conspicuous stimuli awaken

F 1278 Fetal Pain During Prenatal Surgery

the fetus at birth. Fetal sleep can increase painthreshold, but cannot annihilate the possibility of

experiencing pain.

Fetal AnalgesiaIn the case of mayor surgery, some researchers rec-ommend to administer 20microg/kg of intramuscu-

lar fentanyl to the fetus prior to the procedure, to

increase the effect of volatile anesthetics that arriveto it through mother’s circulation (Schwarz and

Galinkin 2003). Recent studies show that direct

administration of 10 microg/kg fentanyl blunts thefetal stress response to intrauterine needling (Fisk

et al. 2001): These authors showed that the magni-

tude of the beta-endorphin response to pain withthese doses was halved, and the cerebral Doppler

response was ablated. Comparison with control

fetuses transfused without fentanyl indicated thatthe beta endorphin and cerebral Doppler response

to intrahepatic vein transfusion with fentanyl

approached that of nonstressful placental cord trans-fusions. Fentanyl significantly attenuated the endor-

phin and cerebrovascular response, but not the

cortisol response (Fisk et al. 2001). This differentialeffect is not surprising. Using the same dose, intra-

venous fentanyl in preterm babies ablated most of

the stress responses to surgery, but the reduction inthe cortisol response after fentanyl failed to achieve

statisticalsignificance(Anandetal.2001). It isworth

highlighting that the amount of opioids that canarrive to the mother from the fetus is clearly low

and relatively safe.

During open fetal surgery under maternalgeneral anesthesia, inhalational agents given to

the mother are still considered to provide adequate

fetal anesthesia and produce uterine relaxationessential for successful surgery, so that additional

analgesia for the fetus would be unnecessary. Nev-

ertheless, several evidences against this approachshould be considered: for instance after cesarean

sections made with maternal general anesthesia,

fetuses are born awake or are easily awakened atbirth, providing evidence that maternal anesthetic

drugs are not sufficiently anesthetic to the fetus.

Endoscopic procedures performed directly onthe fetus, such as tracheal occlusion or

meningomyelocele repair, are usually performed

under maternal local or regional anesthesia.

As these procedures do not requirematernal generalanesthesia, additional fetal anesthesia is desired and

is usually done by direct administration of opioidsand muscle relaxants to the fetus. Two possible

routes of administration for these drugs are injection

into the umbilical cord and intramuscular injectioninto the fetus. Sometimes direct fetal administration

of fentanyl and pancuronium is sometimes limited

to caseswhere the fetusmoves during the procedurein other cases, it is given routinely (Sutton 2008).

Some researchers utilized intra-amniotic opioids

for fetal analgesia on lamb fetuses: They showedthat greater plasma concentrations were obtained in

the fetal lamb as comparedwith the ewe, suggesting

that this route might be utilizable for humans.The presence of an active cortical subplate

(Anand et al. 2001) and of spino-thalamic con-

nections seem sufficient to transmit the painfulstimulus during the second half of pregnancy.

Thus, the use of fetal analgesia is at least a due

precautionary procedure.

Summary

In the second trimester of gestation, the incom-

plete development of the cortex does not yetconsent awareness, but this does not seem to be

an absolute obstacle to pain from the 20th week

of GA. Evidence is present in adult patients forskills that do not need an involvement of the

cortex. Several stimuli are processed without the

need of the cortex (Mulckhuyse and Theeuwes2010); nevertheless, these stimuli give useful

visual information to the individual (Sewards

and Sewards 2000; Pasley et al. 2004), or provokecomplex experiences such as fear (Ohman et al.

2007). A typical example of this is the perception

of fearful stimuli or of unusual objects(for instance, during a mechanical skill like driv-

ing a car) that do not arrive to awareness, but

that nevertheless can provoke complex reactionsor behaviors: These stimuli do not arrive to

awareness, but can affect consciousness. We

can hypothesize a similar scenario for subcorticalfetal processing of pain in this trimester:

After the 20th week of GA, we should not

exclude that pain can be felt by the fetus

Fetal Pain During Prenatal Surgery 1279 F

F

(Mahieu-Caputo et al. 2000), with possible long-term consequences (Lowery et al. 2007).

In the second half of pregnancy, fetuses havea higher pain threshold due to their sleep state,

but this does not absolutely rule out pain. The

presence of thalamocortical pathways and of thecortical subplate point out the possibilities of pain

at this stage of development.

References

Anand, K. J., & Sippel, W. G. (2001). Aynsley green a:Randomized trial of fentanyl anesthesia in pretermbabies undergoing surgery: Effects on the stressresponse. Lancet, 1, 62–66.

Blackburn, S. T. (2003). Maternal, fetal, and neonatalphysiology (2nd ed.). Philadelphia: WB Saunders.

Denton, D. A., McKinley, M. J., Farrell, M., & Egan, G. F.(2009). The role of primordial emotions in the evolu-tionary origin of consciousness. Consciousness andCognition, 18(2), 500–514.

Desborough, J. P. (2000). The stress response to trauma andsurgery. British Journal of Anaesthesia, 85, 109–117.

Fisk, N. M., Gitau, R., Teixeira, J. M., Giannakou-lopoulos, X., Cameron, A. D., & Glover, V. A.(2001). Effect of direct fetal opioid analgesia on fetalhormonal and hemodynamic stress response to intra-uterine needling. Anesthesiology, 95(4), 828–835.

Fitzgerald, R. D., Hieber, C., Schweitzer, E., Luo, A.,Oczenski, W., & Lackner, F. X. (2003). Intraoperativecatecholamine release in brain-dead organ donors isnot suppressed by administration of fentanyl.European Journal of Anaesthesiology, 20, 952–956.

Giannakoulopoulos, X., Sepulveda, W., Kourtis, P.,Glover, V., & Fisk, N. M. (1994). Fetal plasma cortisoland betaendorphin response to intrauterine needling.Lancet, 344, 77–81.

Giannakoulopoulos, X., Teixeira, J., Fisk, N., & Glover,V. (1999). Human fetal and maternal noradrenalineresponses to invasive procedures. Pediatric Research,45, 494–499.

Johnson, M. H. (2005). Subcortical face processing.Nature Reviews Neuroscience, 6(10), 766–774.

Kostovic, I., & Goldman-Rakic, P. S. (1983). Transientcholinesterase staining in the mediodorsal nucleus ofthe thalamus and its connections in the developinghuman and monkey brain. The Journal of ComparativeNeurology, 219, 431–447.

Leader, L. R., & Fifer,W. P. (1995). The potential value ofhabituation in the prenate. In J. P. Lecanuet (Ed.),Fetal development: A psychobiological perspective(pp. 83–404). Hillstdale, NJ: Lawrence Erlbaum.

Lowery, C. L., Hardman, M. P., Manning, N., Hall, R. W.,Anand, K. J., & Clancy, B. (2007). Neurodevelopmentalchanges of fetal pain. Semin Perinatol, 31(5), 275–82.

Mahieu-Caputo, D., Dommergues, M., Muller, F., &Dumez, Y. (2000). Fetal pain. Presse Medicale,29(12), 663–669.

Marın-Padilla, M. (1997). Developmental neuropathologyand impact of perinatal brain damage. II: White matterlesions of the neocortex. Journal of Neuropathologyand Experimental Neurology, 56(3), 219–235.

Merker, B. (2007). Consciousness without a cerebral cor-tex: A challenge for neuroscience and medicine. TheBehavioral and Brain Sciences, 30, 63–81.

Mulckhuyse, M., & Theeuwes, J. (2010). Unconsciousattentional orienting to exogenous cues: A review ofthe literature. Acta Psychologica, 134(3), 299–309.

Ohman, A., Carlsson, K., Lundqvist, D., & Ingvar, M.(2007). On the unconscious subcortical origin ofhuman fear. Physiology & Behavior, 92(1–2), 180–185.

Pasley, B. N., Mayes, L. C., & Schultz, R. T. (2004).Subcortical discrimination of unperceived objects dur-ing binocular rivalry. Neuron, 42(1), 163–172.

Pillai, M., & James, D. (1990). Behavioural states innormal mature human fetuses. Archives of Disease inChildhood, 65(1), 39–43. Spec No.

Rodeck, C. H., & Whittle, M. J. (2008). Fetal medicine:Basic science and clinical practice. London: ElsevierHealth Sciences.

Schwarz, U., & Galinkin, J. L. (2003). Anesthesia for fetalsurgery. Seminars in Pediatric Surgery, 12(3), 196–201.

Sewards, T. V., & Sewards, M. A. (2000). Visual aware-ness due to neuronal activities in subcortical struc-tures: A proposal. Consciousness and Cognition,9(1), 86–116.

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Sutton, L. N. (2008). Fetal surgery for neural tube defects.Best Practice & Research Clinical Obstetrics &Gynaecology, 22(1), 175–188.

Takada, K., Shiota, M., Ando, M., Kimura, M., &Inoue, K. (1989). Porencephaly and hydranencephaly:A neuropathological study of four autopsy cases.Brain & Development, 11(1), 51–56.

Wilken, B., & Gortner, L. (2000). Early auditory evokedpotentials in very small premature infants. Zeitschriftf€ur Geburtshilfe und Neonatologie, 204(1), 14–19.

Wilson, R. D., Lemerand, K., Johnson, M. P., Flake,A. W., Bebbington, M., Hedrick, H. L., & Adzick,N. S. (2010). Reproductive outcomes in subsequentpregnancies after a pregnancy complicated by openmaternal-fetal surgery (1996–2007). American Jour-nal of Obstetrics and Gynecology, 203(3), 209e1–209–e6.

Yoneyama, Y., Sawa, R., Suzuki, S., Shin, S., Power,G. G., & Araki, T. (1996). The relationship betweenuterine artery Doppler velocimetry and umbilicalvenous adenosine levels in pregnancies complicatedby preeclampsia. American Journal of Obstetrics andGynecology, 174(1Pt 1), 267–271.

F 1280 Fetal Pain During Prenatal Surgery

Yoneyama,Y.,Suzuki,S.,Sawa,R.,Takeuchi,T.,Kobayashi,H., Takei, R., Kiyokawa, Y., Otsubo, Y., Hayashi, Z., &Araki, T. (2000). Changes in plasma adenosine concen-trations during normal pregnancy. Gynecologic andObstetric Investigation, 50(3), 145–148.

Fibroblast

Definition

Fibroblast is a connective tissue cell.

Cross-References

▶Wallerian Degeneration

Fibrocartilage

Definition

Fibrocartilage is cartilage that is largely composedof fibers like those in ordinary connective tissue.

Cross-References

▶ Sacroiliac Joint Pain

Fibromyalgia

David Vivian1 and Nikolai Bogduk21Metro Spinal Clinic, South Caulfield, VIC,

Australia2University of Newcastle, Newcastle Bone &Joint Institute, Royal Newcastle Centre,

Newcastle, NSW, Australia

Synonyms

Chronic widespread pain; Fibrositis; Muscular

rheumatism; Psychogenic rheumatism

Definition

Fibromyalgia is a condition characterized by

chronic widespread pain, fatigue, unrefreshedsleep, and a tendency to experience generalized

somatic symptoms.

Characteristics

Fibromyalgia is present in about 5 % of the

population. It is a syndrome of symptoms

that include chronic widespread pain, fatigue,disordered sleep, and increased stress in associa-

tion with abnormal neurosensory processing

and nonspecific endocrine and autonomicdysfunction.

The original American College of Rheumatol-

ogy (ACR) classification criteria for fibromyalgiaincluded tenderness on pressure palpation at 11 or

more of 18 specific tender points (Wolfe et al.

1990). Subsequently, the recognition that exami-nation for tender points lacks validity and reli-

ability has lead to the deletion of tender point

examination from the diagnostic formulation forfibromyalgia.

Fibromyalgia is now a symptom-based diag-

nosis with the primary feature being wide-spread pain present for at least 3 months in

association with other symptoms including

fatigue, non-restorative sleep (NRS), and“somatic” symptoms such as anxiety, irritable

bowel and bladder syndrome, cognitive ineffi-

ciency, tinnitus, and nausea. Justification forthe shift from the physical examination crite-

rion has been elicited by large studies that have

developed diagnostic classification criteriascales. The ACR has now combined the wide-

spread pain index (WPI) and the symptom

severity (SS) scale to produce “simple, practi-cal criteria for the clinical diagnosis of fibro-

myalgia” (Wolfe et al. 2010).The Symptom Intensity Scale (SIS) is

another scoring system for fibromyalgia

(Wilke 2009). It combines the number of areasof pain present in the previous 7 days with

a subjective measurement of fatigue as indi-

cated on a 10-cm line to produce an overall

Fibromyalgia 1281 F

F

SIS score, the level of which categorizespatients with possible fibromyalgia as having

features “probably consistent with fibromyal-gia” or “diagnostic.”

PathophysiologyThe pathophysiology of fibromyalgia is unknown

and remains in dispute. Patients with fibromyal-

gia exhibit increased pain sensitivity to pressure,heat, cold, and electrical stimulation, but these

features are not unique to fibromyalgia (Gracely

et al. 2003).Other markers of the disorder have been

explored, but the results have not been consistent

or reproducible. Nor are the abnormalities, whenevident, expressed by all patients with fibromy-

algia. Nor are they unique to these patients.

NRS, which is defined variably but includesthe feeling of being unrefreshed upon awakening

in spite of normal sleep duration, is common in

the general population but more prevalent in FMand chronic fatigue syndrome (CFS) (Staud

2010). Fragmented sleep or difficulty getting to

sleep is also common in FM patients. Althoughnot unique to NRS, ▶ alpha(a)-delta(d) sleep is

more common in subjects with NRS than in

healthy controls. The same anomaly occurs inother conditions and in 15 % of healthy individ-

uals (Carette 1995). Histological abnormalities

have been reported in the muscles of patientswith fibromyalgia, but no differences have been

found in adequately controlled studies (Carette

1995). Nor have disturbances in muscle metabo-lism been verified (Carette 1995). Patients with

fibromyalgia exhibit deficiencies in ▶ serotonin,

increased levels of ▶ substance P in their cere-brospinal fluid, and abnormalities of the ▶ hypo-

thalamic pituitary axis (Carette 1995), but these

differences have not been shown to be unique tofibromyalgia.

One model that has been proposed is that

fibromyalgia is due to an impairment of thediffuse noxious inhibitory control system

(DNIC) (Gracely et al. 2003). The implication

is that patients perceive spontaneous painbecause of a lack of tonic inhibition of the cen-

tral nociceptive pathways. The circumstantial

evidence is that of conditioning, that painful

stimuli produce analgesia in normal subjectsbut fail to do so in patients with fibromyalgia

(Gracely et al. 2003).Although this may be so, commentators have

questioned whether the syndrome is due to

altered central nociception or to hypervigilance,and if there is altered nociception, does it arise

because of somatic factors or psychogenic influ-

ences (Cohen and Quintner 1998).

NosologyThe relegation of tenderness as a diagnostic cri-terion for diagnosis of fibromyalgia together with

the development of symptom-based standards

has provided clinicians with a more robust andreliable method for managing and studying

patients with these symptoms. As a minimum,

the diagnosis of fibromyalgia offers patientsa diagnostic label that is more palatable than

a diagnosis of widespread pain (Carette 1995).

TreatmentA variety of treatments have been applied to

patients with fibromyalgia. Many treatments arebased on hearsay or anecdote, and some of the

conclusions from studies are based on previous

diagnostic criteria for fibromyalgia. The EULARreport in 2008 found 146 studies eligible for

review and made 9 recommendations for the man-

agement of fibromyalgia (Carville 2008). Exercisein general including heated pool exercise had

some limited evidence and was included on the

basis of expert opinion; tramadol had benefits over13 weeks in a randomized controlled trial, but

simple analgesics were supported and opioids

refuted by expert opinion; antidepressants tendedto reduce pain and improve function over a 12-

week period but not over longer periods.

A multidisciplinary approach to managementwas considered relevant, but this was again based

on expert opinion rather than any evidence.

Ameta-analysis of pregabalin found five high-quality trials (Straube 2010). Pregabalin seems to

have similar efficacy to other medication treat-

ments including duloxetine, combined paraceta-mol and tramadol, and amitriptyline 25 mg/day.

Pregabalin enhances slow-wave sleep, and

sodium oxybate (gamma-hydroxybutyrate)

F 1282 Fibromyalgia

reduces alpha EEG sleep, and both may havea role in symptomatic control of FM for those

reasons (Staud 2010).

Cross-References

▶Chronic Low Back Pain: Definitions and

Diagnosis▶ Fibromyalgia, Mechanisms, and Treatment

▶Human Thalamic Response to Experimental

Pain (Neuroimaging)▶Muscle Pain, Fibromyalgia Syndrome

(Primary, Secondary)

▶Myalgia▶Nocifensive Behaviors, Muscle and Joint

▶Opioids and Muscle Pain

▶ Physical Exercise▶ Psychological Aspects of Pain in Women

References

Carette, S. (1995). Fibromyalgia 20 years later. What havewe accomplished? The Journal of Rheumatology, 22,590–594.

Carville, S. F., Arendt-Nielsen, S., Bliddal, H., et al.(2008). EULAR evidence-based recommendationsfor the management of fibromyalgia syndrome. Annalsof the Rheumatic Diseases, 67, 536–541.

Cohen, M. L., & Quintner, J. L. (1998). Fibromyalgia syn-drome and disability: A failed construct fails those inpain.TheMedical Journal of Australia, 168(8), 402–404.

Gracely, R. H., Grant, M. A. B., & Giesecke, T. (2003).Evoked pain measures in fibromyalgia. Best Practice& Research Clinical Rheumatology, 17, 593–609.

Staud, S. (2010).Nonrestorative sleep in fibromyalgia: Fromassessment to therapy – focus on diagnosis. Medscape.http://cme.medscape.com.viewarticle/727292

Straube, S., Derry, S., Moore, R. A., et al. (2010).Pregabalin in fibromyalgia: Meta-analysis of efficacyand safety from company clinical trial reports. Rheu-matology, 49, 706–715.

Wilke,W. S. (2009). New developments in the diagnosis offibromyalgia syndrome: Say goodbye to tender points?Cleveland Clinic Journal of Medicine, 76, 345–352.

Wolfe, F., Smythe, H. A., Yunus, M. B., et al. (1990). TheAmerican college of rheumatology 1990 criteria forthe classification of fibromyalgia. Arthritis & Rheuma-tism, 33, 160–172.

Wolfe, F., Clauw, D. J., Fitzcharles, M., et al. (2010). TheAmerican college of rheumatology preliminary diag-nostic criteria for fibromyalgia and measurement ofsymptom severity. Arthritis Care & Research, 62,600–610.

Fibromyalgia Syndrome

▶Muscle Pain, Fibromyalgia Syndrome(Primary, Secondary)

Fibromyalgia, Mechanisms, andTreatment

Alice A. Larson and Katalin J. Kovacs

Department of Veterinary and BiomedicalSciences, University of Minnesota, St. Paul,

MN, USA

Introduction

Historically, fibromyalgia syndrome (FMS) was

referred to as fibrositis, a term coined by Sir

Edward Gowers at the turn of the century todescribe the inflammation responsible for the

stiffness and pain experienced by a group of

non-arthritic patients. Fibromyalgia syndromewas the name adopted in 1990 by the American

College of Rheumatology (Wolfe et al. 1990),

and the consensus document on fibromyalgia atthe MYOPAIN conference held in Copenhagen,

Denmark, in 1992 provided the original descrip-tion of the syndrome, the diagnostic criteria, and

its prevalence. More recently, the American

College of Rheumatology has provisionallyapproved a revised set of criteria for the diagnosis

of fibromyalgia that does not require a tender

point assessment (Wolfe et al. 2010).

Definition

Many chronic pain conditions display symptoms

that overlap with those of FMS. Those conditionsmust be diagnosed separately and eliminated as

the first step in the diagnostic protocol. The diag-

nostic criteria include widespread pain in allfour quadrants of the body for a minimum of

3 months, originally based on tenderness to dig-

ital palpation at 11 of the 18 anatomically defined

Fibromyalgia, Mechanisms, and Treatment 1283 F

F

tender points that are sensitive to pressure(mechanical pain). Wolfe et al. (2010) now rec-

ommend the diagnosis be based on the combina-tion of a widespread pain index (WPI) and

a symptom severity scale (SS) as follows: (WPI

" 7 and SS " 5) or (WPI 3–6 and SS "9).Reductions in electrical and thermal pain thresh-

olds have also been reported in patients with

FMS, suggesting multimodal changes in painsensitivity.

Characteristics

PrevalenceIn North America, approximately 2 % of the

population, or greater than 3.7 million people,

are estimated to suffer from FMS. The majorityof these patients, approximately three out of four,

are female. While it is the second most common

syndrome presented in rheumatology clinics, thetreatment is typically unsatisfactory, resulting in

disability and handicap. Studies in several coun-

tries and ethnicities suggest a poor prognosis overseveral years of treatment.

ComorbidityChronic widespread pain is the primary com-

plaint bringing most patients with FMS into the

clinic. In addition to pain, non-restorative sleep,fatigue, anxiety and depression, interstitial cysti-

tis, and irritable bowel syndrome are symptoms

frequently diagnosed in patients with FMS.A higher incidence of cold intolerance, restless

leg syndrome, cognitive dysfunction, rhinitis, and

multiple chemical sensitivities is also more com-mon in FMS patients than in healthy normal

controls, adding to the perplexing mosaic of the

disease. The etiology of FMS is unknown, and therelationships between pain and the other symp-

toms of FMS are unclear. Acute pain usually

results in increased activation of the pituitary-adrenal and sympathomedullary pathways as

well as growth hormone production. Patients

with FMS, in contrast, present with hypofunctionof the HPA, thyroidal, and gonadal axis; dimin-

ished growth hormone production (reviewed by

Bennett 1998); and abnormally low sympathetic

output (Clauw and Chrousos 1997). While expo-sure to stressful situations, including noise, lights,

and weather, exacerbates symptoms of FMS,patients have an impaired ability to activate the

hypothalamic-pituitary portion of the HPA axis

as well as the sympathoadrenal system, leading toreduced adrenocorticotropic hormone (ACTH)

and epinephrine responses. Yet many symptoms

of FMS are sympathetically maintained, such asthe neuropathic-type pain (reviewed by

Martinez-Lavin 2007), abnormal heart rate

variability, tilttable responses, and inappropriateresponses to daily stressful situations.

Unique Location of Tender PointsWhile tender points are no longer necessary

diagnostically, they offer insight into the etiol-

ogy of pain. Tender points are generally distrib-uted in areas whose primary afferent nerves

project to spinal lumbar levels 3–5 and cervical

levels 2–7 spinal cord segments. It may be ofimportance that these areas surround the tho-

racic 1 through lumbar 3 spinal cord segments

that are involved with regulation of the sympa-thetic nervous system, whose function is signif-

icantly altered in patients with FMS. It is

noteworthy that the pain of FMS is often inareas that receive a relatively low density of

afferent innervation (trunk and proximal limbs)

compared to areas normally considered “sensi-tive” by virtue of their dense innervation, e.g.,

the fingers, mouth, feet, and genitals. The sensi-

tivity of these tender points does not, then, orig-inate from a simple hyperactivity of all

mechanically sensitive tissues but rather from

an unknown, symmetrically distributed changein afferent input. Based on this and other psy-

chophysical evidence of windup, the etiology of

this syndrome is widely believed to includethe CNS.

Excitatory Amino AcidsExcitatory amino acids, such as glutamate and

aspartate, transmit pain signals, including those

in patients with FMS.While the concentrations ofmost amino acids in the cerebrospinal fluid do not

differ between subjects with FMS compared to

healthy normal controls, a high degree of

F 1284 Fibromyalgia, Mechanisms, and Treatment

correspondence was found between specificamino acids and the degree of pain reported at

the 18 tender points (tender point index, TPI).Excitatory amino acid activity is known to trigger

synthesis of nitric oxide (NO), a gaseous-

signaling compound that is critical for the devel-opment and expression of chronic pain.

Enhanced synthesis of NO results from a variety

of depolarizing events, including excitatoryamino acid and substance P activity, both of

which lead to influx of calcium and activation of

the enzyme NO synthase. NMDA activity is alsoassociated with the production of nerve growth

factor (NGF), a compound that regulates the syn-

thesis of peptides in primary afferent C-fiberssuch as substance P.

Substance PThe first documentation of a biochemical charac-

teristic consistent with chronic pain in patients

with FMS was the increased concentration ofsubstance P in their cerebrospinal fluid (Vaeroy

et al. 1988; Russell et al. 1994;Welin et al. 1995),

similar to that in many other pain states. Sub-stance P is a neuroactive peptide released from

small-diameter, unmyelinated primary afferent

fibers, called nociceptors. Substance P isupregulated in chronic, inflammatory pain condi-

tions by increased concentrations of NGF.

Because substance P does not mediate acutepain but supports hyperalgesia, enhanced sub-

stance P content in the cerebrospinal fluid of

patients with FMS is consistent with a chronichyperalgesic state.

Growth FactorsSynthesis of nerve growth factor (NGF),

a neurotrophin, in inflamed tissue is responsible

for the upregulation of SP synthesis duringchronic pain and the development of mechanical

hyperalgesia and allodynia. Intravenous adminis-

tration of NGF in humans causes muscle pain ina dose-dependent manner, primarily in bulbar

and truncal musculature, and affects women

more than men. While there is no gross inflam-mation at tender points to account for a peripheral

source of NGF, delivery of NGF to the spinal area

of mice or rats is sufficient to cause hyperalgesia.

The concentration of NGF in the cerebrospinalfluid is normally low or unmeasurable in healthy

individuals, but NGF is elevated in patients withprimary but not secondary FMS (Giovengo et al.

1999). In addition, the concentration of brain-

derived neurotrophic factor (BDNF), a mediatorof pain in the peripheral nervous system, is ele-

vated in the serum of patients with FMS (Laske

et al. 2007). It is, therefore, possible that elevatedconcentrations of NGF and or BDNF are respon-

sible for the hyperalgesia and allodynia associ-

ated with FMS, while secondary FMS resultsfrom conditions producing large areas of

enhanced pain sensitivity.

FMS and Thalamic ActivityPositron emission tomography (PET) and func-

tional magnetic resonance imaging (fMRI) stud-ies in humans indicate that the thalamus as well as

the anterior insula and S2 area are important in

the perception of pain. Activation of the thalamusby pain normally initiates descending inhibitory

activity that controls pain. Stimulation of

the somatosensory thalamus has even been suc-cessfully used to treat extreme conditions of

chronic pain in humans. Descending activity

originating from the thalamus is sufficientlyimportant that thalamotomy in rats results in

both thermal as well as mechanical hyperalgesia.

Although pain normally stimulates the thalamusin healthy individuals, a different pattern of acti-

vation occurs in patients with chronic pain.

Regional blood flow in response to painful stim-ulation also differs in patients with FMS com-

pared to that in normal control individuals

(Risberg et al. 1995; Mountz et al. 1998; Petzkeet al. 2000). These studies suggest that either the

ascending spinothalamic nociceptive pathways

are not fully functional or the thalamus respondsabnormally to input from spinothalamic neurons.

Because other parts of the CNS respond appro-

priately in patients with FMS, ascending activityappears sufficient. Rather, thalamic neurons

likely fail to initiate sufficient descending inhib-

itory activity controlling nociceptive processingat the spinal cord level, a concept supported by

altered nociceptive responses in patients with

FMS (Staud et al. 2003).

Fibromyalgia, Mechanisms, and Treatment 1285 F

F

TreatmentA variety of muscle relaxants, sedatives, analge-

sics, and drugs that promote sleep or combat

fatigue are frequently used to treat symptoms ofFMS. Unfortunately, even nonnarcotic analgesic

drugs provide only temporary relief in most

patients. When all else fails, narcotic analgesicsare transiently effective in controlling flares, but

not only does tolerance develop to their analgesic

effect but long-term use can unmask an opioid-induced hyperalgesia. The efficacy and side

effects of each compound vary greatly from one

patient to another, but in general, their sideeffects are minimized and efficacy maximized

by combination treatments using two drugs with

distinct mechanisms of action. For example,gabapentin (Neurontin) is a compound used for

neurogenic pain either alone or in combination

with opioids. Gabapentin inhibits calcium chan-nel activity, thereby minimizing the release of

neurotransmitters.

Low doses of tricyclic antidepressants, such asamitriptyline, provide immediate but temporary

analgesia, similar to their efficacy in other

chronic pain conditions (O’Malley et al. 2000).The efficacy of this, and related drugs, is likely

due to their action on nociceptive pathways and is

not related to their antidepressant activity, whichrequires higher doses and longer periods of treat-

ment to develop. Because tolerance to their anal-gesic activity develops, low doses (10 mg or less)

are recommended in the beginning, gradually

increasing by 10 mg as needed until the optimaldose of 70–80 mg is reached.

Only pregabalin (Lyrica), duloxetine

(Cymbalta), and milnacipran (Savella) are FDAapproved for the treatment of FMS symptoms.

Duloxetine and milnacipran are antidepressants

that inhibit serotonin and norepinephrine reup-take. Over the short term, this increases the syn-

aptic concentration of these transmitters but, by

doing so, influences their receptor sensitivityover the long term. In contrast, pregabalin binds

to a voltage-dependent calcium channel in the

central nervous system, reducing calcium influxinto the nerve terminals and decreasing release of

neurotransmitters such as glutamate, noradrena-

line, and substance P. Pregabalin also increases

the concentration of GABA, an inhibitory neuro-transmitter, by increasing glutamic acid decar-

boxylase activity, the enzyme required for thesynthesis of GABA.

Drug treatment to temporarily alleviate pain,

including amitriptyline, NSAIDS, and evennarcotic analgesics, should be geared to facili-

tate a new level of physical activity (reviewed

by Clauw and Crofford 2003) as the most effec-tive treatment for FMS is exercise (Sim and

Adams 2002). Patients need to understand that

exercise is the key to recovery, even if thismeans merely doubling their distance walked

within the house from one day to the next. The

exercise program should be initiated gradually,or it will temporarily exacerbate their symp-

toms. Heat therapy, in the form of a long hot

bath immediately prior to bedtime, has beenanecdotally reported to be effective for epi-

sodic bouts of intense pain. In contrast, cold

exacerbates their condition and should beavoided.

Cross-References

▶Chronic Low Back Pain: Definitions andDiagnosis

▶Disability in Fibromyalgia Patients

▶ Fibromyalgia, Mechanisms, and Treatment▶Human Thalamic Response to Experimental

Pain (Neuroimaging)

▶Muscle Pain, Fibromyalgia Syndrome(Primary, Secondary)

▶Myalgia

▶Nocifensive Behaviors, Muscle and Joint▶Opioids and Muscle Pain

▶ Physical Exercise

▶ Psychological Aspects of Pain in Women

References

Bennett, R. M. (1998). Disordered growth hormone secre-tion in fibromyalgia: A review of recent findings anda hypothesized etiology. Zeitschrift f€urRheumatologie, 57(Suppl 2), 72–762.

Clauw, D. J., & Chrousos, G. P. (1997). Chronic pain andfatigue syndromes: Overlapping clinical and

F 1286 Fibromyalgia, Mechanisms, and Treatment

neuroendocrine features and potential pathogenicmechanisms. Neuroimmunomodulation, 4, 143–1533.

Clauw, D. J., & Crofford, L. J. (2003). Chronic widespreadpain and fibromyalgia: What we know, and what weneed to know. Best Practice & Research ClinicalRheumatology, 17, 685–7014.

Giovengo, S. L., Russell, I. J., & Larson, A. A. (1999).Increased concentrations of nerve growth factor incerebrospinal fluid of patients with fibromyalgia.Journal of Rheumatology, 26, 1564–15695.

Laske, C., Stransky, E., Eschweiler, G. W., et al. (2007).Increased BDNF serum concentration in fibromyalgiawith or without depression or antidepressants. Journalof Psychiatric Research, 41, 600–605.

Martinez-Lavin, M. (2007). Stress, the stress responsesystem, and fibromyalgia. Arthritis Research &Therapy, 9, 216.

Mountz, J. M., Bradley, L. A., & Alarcon, G. S. (1998).Abnormal functional activity of the central nervoussystem in fibromyalgia syndrome. The AmericanJournal of the Medical Sciences, 315, 385–3968.

O’Malley, P. G., Balden, E., Tomkins, G., et al.(2000). Treatment of fibromyalgia with antidepres-sants. Journal of General Internal Medicine, 15,659–666.

Petzke, F., Clauw, D. J., Wolf, J. M., & Gracely, R. H.(2000). Pressure pain in fibromyalgia and healthy con-trols: Functional MRI subjective pain experienceversus objective stimulus intensity. Arthritis andRheumatism, 43, 200010.

Risberg, J. G., Rosenhall, U., Orndahl, G., et al. (1995).Cerebral dysfunction in fibromyalgia: Evidence fromregional cerebral blood flow measurements,otoneurological tests and cerebrospinal fluid analysis.Acta Psychiatrica Scandinavica, 91, 86–9411.

Russell, I. J., Orr, M. D., Littman, B., et al. (1994).Elevated cerebrospinal fluid levels of substance P inpatients with the fibromyalgia syndrome. Arthritis andRheumatism, 37, 1593–160112.

Sim, J., & Adams, N. (2002). Systematic review of ran-domized controlled trials of nonpharmacological inter-ventions for fibromyalgia. The Clinical Journal ofPain, 18, 324–33613.

Staud, R., Robinson, M. E., Vierck, C. J., et al. (2003).Diffuse noxious inhibitory controls (DNIC) attenuatetemporal summation of second pain in normal malesbut not in normal females or fibromyalgia patients.Pain, 101, 167–17414.

Vaeroy, H., Helle, R., Forre, O., et al. (1988). ElevatedCSF levels of substance P and high incidence ofRaynaud’s phenomenon in patients withfibromyalgia: New features for diagnosis. Pain,32, 21–2615.

Welin, M., Bragee, B., Nyberg, F., et al. (1995). Elevatedsubstance P levels are contrasted by a decrease in met-enkephalin-arg-phe levels in CSF from fibromyalgiapatients. Journal of Musculoskeletal Pain, 3, 4.

Wolfe, F., Clauw, D. J., Fitzcharles, M.-A., et al. (2010).The American college of rheumatology preliminary

diagnostic criteria for fibromyalgia and measurementof symptom severity. Arthritis Care & Research, 62,600–610.

Wolfe, F., Smythe, H. A., Yunus, M. B., et al. (1990). TheAmerican college of rheumatology 1990 criteria forthe classification of fibromyalgia. Report of the multi-center criteria committee. Arthritis and Rheumatism,33, 160–172.

Fibrositis

▶ Fibromyalgia▶Myalgia

▶ Psychiatric Aspects of the Epidemiology ofPain

Fibrositis Syndrome

▶Muscle Pain, Fibromyalgia Syndrome

(Primary, Secondary)▶Myalgia

Field Block

Definition

Local anesthetic injected through intact skin

adjacent to the surgical site to createa subcutaneous wall encompassing the injury.

Cross-References

▶Acute Pain in Children, Postoperative

Fifth Lobe

▶ Insular Cortex, Neurophysiology, and Func-

tional Imaging of Nociceptive Processing

Fifth Lobe 1287 F

F

Firing of Suburothelial AfferentNerves

Definition

Firing of suburothelial afferent nerves and thethreshold for bladder activation may be modified

by both inhibitory (e.g., NO) and stimulatory (e.g.,

ATP, tachykinins, prostanoids) mediators. Thesemechanisms can be involved in the generation of

detrusor overactivity causing urgency, frequency,

and incontinence, but also bladder pain.

Cross-References

▶Opioids and Bladder Pain/Function

First and Second Pain

Definition

When a needle is pierced into the skin of an extrem-

ity, the subject feels typically an immediate sting-ing pain followed after a short delay by a second

wave of predominantly burning pain. These two

pain phenomena are called “first” and “second”pain. They are attributed to the excitation of A-

delta and C-fibers. Since the former have conduc-

tion velocities up to 30 m/s, the nerve impulsesreach the central nervous system so quickly that

no delay is experienced. C-fibers having conduc-

tion velocities around 1 m/s convey their impulsesconsiderably slower. If the needle prick is applied

to the foot of a grown-up person, the delay could be

more than a second. If the sting is applied to theface, the two pains are not separated by a delay due

to the short conductance distance.

Cross-References

▶Encoding of Noxious Information in the SpinalCord

▶Opioids, Effects of Systemic Morphine on

Evoked Pain

First and Second Pain Assessment(First Pain, Pricking Pain, Pin-PrickPain, Second Pain, Burning Pain)

Donald D. PriceOral Surgery and Neuroscience, McKnight Brain

Institute University of Florida, Gainesville,

FL, USA

Synonyms

Burning pain; First pain assessment; Pin-prickpain; Pricking pain; Second pain assessment

Definition

Prior to the development of methods for physio-logical and anatomical characterization of axons

within peripheral nerves, Henry Head concluded

that the skin was served by epicritic and proto-pathic afferent systems in which each gave rise to

its own particular qualities of sensations (Head

1920). Epicritic pain, for example, was said to beaccurately localized, to not outlast the stimulus,

and to provide precise qualitative information

about the nature of the stimulus. Thus, epicriticpain could be elicited by mild pricking of the skin

with a needle, a form of pain known to almost

everyone as pricking pain. In contrast, proto-pathic pain was described as less well localized,

slow in onset, often outlasting the stimulus, and

summating with repeated stimulus application.Protopathic pain was considered more difficult

to endure and contained special feelings of

unpleasantness or “feeling tone.” The concept of“protopathic” has been applied to burning pain,

aching pain, throbbing pain, and dull pain. Head

based these ideas largely on observations made ofhis own experiences of pain, after nerve division

and during nerve regeneration.

With the advent of modern electrophysiologi-cal and neuroanatomical techniques, it became

clear that pain depended on two types of periph-

eral nerve axons. The first is that of thinly mye-linated A-delta axons, whose conduction

F 1288 Firing of Suburothelial Afferent Nerves

velocities range between 3 and 30 m/s, and thesecond is that of unmyelinated C axons, whose

conduction velocities range between 0.5 and2.0 m/s. Based on their differences in conduction

velocity and reminiscent of the functional dichot-

omy proposed by Head, Zotterman proposed thatA-delta and C afferent axons could account for

first and second pain, which often occur in

response to a brief intense stimulus to the handor foot (Zotterman 1933). Landau and Bishop

explicitly related first pain to epicritic pain and

second pain to protopathic pain (Landau andBishop 1953). Interestingly, they based their con-

clusions as a result of an approach similar to that

of Head. They carefully observed and recordedtheir own pain experiences in response to “exper-

imental” pain stimuli, before and after selective

conduction block of A-delta or C axons of periph-eral nerves. They used local injections of dilute

solutions of procaine to selectively block C axons

within small nerve branches in order to study painfrom impulses in A-delta axons. They selectively

blocked all myelinated axons in peripheral nerves

of their lower arms by means of a 250 mmHgpressure cuff in order to assess the types of pains

evoked by impulses in C axons. They applied

various types of painful stimuli to skin, fascia,and periosteal surfaces, including bee stings, tur-

pentine injections, intramuscular KCL injections,

and application of deep and sharp pressure withmechanical probes. When they blocked C axons

with procaine, well-localized brief-duration

stinging sharp pains, such as those elicited bypinpricks (i.e., pricking pain or first pain), were

preserved, but prolonged, deep, and diffuse burn-

ing pains evoked by inflammatory stimuli, suchas the second pain from a bee sting, could no

longer be elicited. When they blocked all mye-

linated (A) axons by means of the blood pressurecuff, the latter types of pain could be elicited and

were more intense than before blockade of mye-

linated axons.These general observations have since been

corroborated in conventional studies, wherein

investigators studied responses of volunteer par-ticipants (Price 1972, 1999; Collins et al. 1960).

An important aspect of the study by Collins et al.

was that compound action potentials were

monitored (Collins et al. 1960). They placedstimulating and recording electrodes under the

sural nerve of cancer patients undergoinganterolateral chordotomy for relief of pain.

They found that stimulation of A-delta axons

produced sharp pricking pain sensations thatwere accurately localized. When A-delta axons

were blocked by cold, stimulation of C axons at

a rate of 3/s resulted in summating unbearablediffuse burning pain that was not as well

localized.

The association of first and second pain withimpulses in A-delta and C axons and the relation-

ship of these two types of pain to epicritic and

protopathic pain have pivotal roles in the historyof pain research. However, like all functional

dichotomies, it is important not to overgeneralize

their explanatory role, for example, to prema-turely label different central pain-related path-

ways as “epicritic” or “protopathic.” Even Head

warned against this type of error, when he con-cluded that epicritic and protopathic systems

recombined once they entered the dorsal horn

(Head 1920). Thus, although zones of relativelypure epicritic or protopathic sensibility could be

found after dorsal root or peripheral nerve

lesions, he noted that such zones were neverobserved after lesions of the spinal cord or

brain. More than 40 years before electrophysio-

logical studies were carried out on dorsal hornnociceptive neurons, Head anticipated the synap-

tic convergence of two functional types of

primary nociceptive afferents (known since asA-delta and C) onto neurons of the dorsal horn.

One must also take note of the fact that A-delta

and C nociceptive afferents are rarely activated inisolation. Most acute pains are likely to reflect

a combination of input from A-delta and

C nociceptive afferents and, in most cases, fromnon-nociceptive afferents as well. Indeed, the

composition of input from different types of noci-

ceptive and non-nociceptive afferents undoubt-edly contributes a lot to the diverse qualities of

both painful and non-painful somatic sensation

(Price 1999). However, many long-durationpains, especially those that are diffuse, spatially

spreading, and especially unpleasant in their

“feeling tone” may depend to a greater extent

First and Second Pain Assessment 1289 F

F

on tonic input from C nociceptive afferents than

from input from A-delta nociceptive afferents.The initial pains from abrupt injuries (e.g.,

stepping on a tack) are likely to depend heavily

on A-delta nociceptive afferents.

Characteristics

Temporal Characteristics of First and SecondPain and Their Relationships to NeuralMechanismsFirst and second pains are often easily distin-

guished when a sudden tissue damaging or poten-tially tissue-damaging stimulus occurs on a distal

part of the body, such as the hand or foot (Fig. 1).

The 0.5–1.5-s delay between the two painsoccurs as a result of the fact that nerve impulses in

Caxons travelmuch slower (0.5–1.5m/s) than those

in thinlymyelinatedA axons (6–30m/s). Lewis andPochin independently mapped the body regions

wherein they experienced both first and second

pains (Lewis and Pochin 1938). The body maps of

both Lewis and Pochin were nearly identical. The

maps showed that first and second pain could beperceived near the elbow but not the lower trunk,

even though both siteswere about the same distance

from the brain. The reason for this difference is thatC fibers that supply the trunk have a short conduc-

tion distance to the spinal cord,whereasCfibers that

supply the skin near the elbow have a long conduc-tion distance. Once both “trunk” and “elbow”

C fibers reach the spinal cord, they synapse on

nerve cells that have fast-conducting axons. Asa result of differences in peripheral conduction dis-

tance and time, first and second pain can be discrim-

inated at the elbow but not the trunk.Later, studies using psychophysical methods

replicated and extended the ones just described

(Price 1972, 1999). These methods relied ondelivering brief and well-controlled experimental

stimuli to the distal part of an extremity, such as

the hand or foot. These regions were chosenbecause they allowed for discrimination of first

and second pain related to impulse conduction inA-delta and C axons, respectively. Reaction time

Pain Ratings of Normal Controls

A) .71 mA/mm2

B) 1.28 mA/mm2

First and Second Pain Intensity

Recording of Spinothalamic Neuron

C-RESP

00

20

20

10NS

40

40

30

20

10

40

30

60

80

100

400 800 1200 1600 2000

2000 25001500

Time (msec)

StimulusOn set

1000500Fr

ee m

agni

tude

est

imat

ion

(Log

mm

)

First and Second Pain Assessment (First Pain,Pricking Pain, Pin-Prick Pain, Second Pain, BurningPain), Fig. 1 (Left) Double response of spinothalamictract dorsal horn neuron to synchronous stimulation ofA-delta and C axons by means of electrical shocks toa cutaneous nerve. The delay between the two

postsynaptic impulse responses is related to the fasterand slower conduction velocities of A and C axons,respectively. (Right) Subjects’ mean ratings of intensitiesof first and second pains. Note similarity of profiles ofneuron responses to pain ratings (Modified from Lewisand Pochin (1938))

F 1290 First and Second Pain Assessment

measurements were used to confirm that subjectscould indeed distinguish the two pains. Both

trained and untrained subjects reported qualities

of first pain as “pricking,” “stinging,” or “sharp”(i.e., pin-prick pain), without provocation or sug-

gestion that such qualities existed. Subjects were

trained to judge the perceived magnitudes of firstand second pain by squeezing a handgrip dyna-

mometer in some experiments (Price et al. 1977)

or using a mechanical visual analogue scale inothers (Price et al. 1994). Mean psychophysical

ratings of intensities of first pain during trains of

computer-driven heat pulses (2.5 s duration, peaktemperature 52#C) decreased progressively

(Price 1999; Price et al. 1977, 1994) and stayedthe same in the case of 5–9 mA electric shocks

(Price 1972; Price et al. 1994). Unlike first pain,second pain progressively increased in mean

intensity and duration throughout a series of

shocks or heat pulses, when the interstimulusinterval was less than 3 s but not when it was

5 s (Price 1972, 1999; Price et al. 1977, 1994)

(Fig. 2). Moreover, second pain became stronger,more diffuse, and more unpleasant with repeated

heat pulses or repeated electrical shocks.

When the same types of heat pulses or electricalshocks described above are applied to the skin of

monkeys, spinothalamic tract neurons within the

spinal cord dorsal horn respond with a doubleresponse (i.e., two sets of impulse discharges)

(Price 1999), as shown in Fig. 1. The earlier of thetwo is related to synaptic input fromA-nociceptors,

First and Second PainAssessment (First Pain,Pricking Pain, Pin-PrickPain, Second Pain,Burning Pain),Fig. 2 Subjects’ meanratings of second pain inresponse to series of 9-mAelectric shocks. Notetemporal summation ofsecond pain at interstimulusintervals of 3 s but not 5 sand the fact that first painremains at the sameintensity throughout seriesof shocks (From Price(1999))

First and Second Pain Assessment 1291 F

F

and the delayed response is related to synaptic inputfrom C nociceptors (Price 1999; Price et al. 1977).

Similar to first pain, the first response decreases orremains the same during heat pulses or shocks,

respectively, whereas the second delayed response

to heat pulses or shocks increases progressivelyboth in magnitude and duration. Similar to second

pain, temporal summation of the delayed neural

response was observed when the interstimulusinterval was 3 s or less but not 5 s (Price 1999).

For neurons, this temporal summation has been

termed “windup” (Price 1999).Moreover, this sum-mation must occur within the spinal cord dorsal

horn because similar experiments conducted on

peripheral A and C nociceptors show that theirresponses do not increase with stimulus repetition

(Price et al. 1977, 1994). Thus, temporal summa-

tion of second pain depends on mechanisms of thecentral nervous system (i.e., dorsal horn neurons),

not changes in peripheral receptors.

These psychophysical-neural parallels havebeen confirmed not only in the case of single

neurons of the spinal cord dorsal horn but also in

the case of neural imaging at the level of thesomatosensory region of the cerebral cortex

(Tommerdahl et al. 1996). Using a brain imaging

method of intrinsic optical density measurements(OIS), Tommerdahl and colleagues (Tommerdahl

et al. 1996) imaged neural activity within the pri-

mary somatosensory cortex of anesthetized squirrelmonkeys as their hands were repetitively tapped

with a heated thermode. These taps reliably evoke

first and second pain in human subjects. Theirmethod of neural imaging has a high degree of

both spatial and temporal resolution, measuring

local cortical neural activity within 50–100 mmand sampling neural activity that has occurred

within a third of a second. Heat taps produced

localized activity in two regions of the primarysomatosensory cortex, termed 3a and 1. When

a train of heat taps was presented at a rate of once

per 3 s, each tap evoked delayed neural activitywithin these regions. The neural response to each

tap grew progressively more intense and larger in

area with each successive tap. This temporal sum-mation of this neural response paralleled human

psychophysical experiences of second pain in sev-

eral distinctways. Both types of responses summate

at the same rate of stimulus repetition and havea similar growth in intensity during a series of

heat taps. The perceived skin area in which secondpain is perceived and the area of cortical neural

activity both increase with repeated heat taps.

Windup and temporal summation of secondpain are related to synaptic interactions between

C-nociceptive afferents and dorsal horn neurons.

These interactions involve long-duration excit-atory processes related to the release of neuro-

transmitters such as glutamate/aspartate and

neuromodulators such as substance P. Theseagents respectively activate NMDA (N-methyl-

D-aspartate) receptors and neurokinin 1 recep-

tors, leading to prolonged depolarizations(Thompson and Woolf 1990, for review). Thus,

NMDA receptor antagonists block both temporal

summation of second pain and the “windup”responses of dorsal horn neurons to repeated

C fiber input (Price 1999). Windup is related to

hyperalgesic states that can be produced experi-mentally as well as those occurring in pathophys-

iological pain, such as postherpetic neuralgia

(Arendt-Nielsen 1997; Dubner 1991). Indeed,slow temporal summation has long been consid-

ered a central neural mechanism that has a role in

pathophysiological pain (Noordenbos 1959).

References

Arendt-Nielsen, L. (1997). Induction and assessment ofexperimental pain from human skin, muscle, and vis-cera. In T. S. Jensen, J. A. Turner, & Z. Wiesenfeld-Hallin (Eds.), Proceedings of the 8th World Congresson pain (pp 393–403). Seattle: IASP Press.

Collins, W. F., Nulsen, F. E., & Randt, C. T. (1960).Relation of peripheral nerve fiber size and sensationin man. Archive of Neurology (Chicago), 3, 381–385.

Dubner, R. (1991). Neuronal plasticity and pain followingperipheral tissue inflammation or nerve injury. In M.Bond, E. Charlton, & C. J. Woolf (Eds.), Proceedings ofVth World Congress on pain. Pain research and clinicalmanagement (Vol.5,pp.263–276).Amsterdam:Elsevier.

Head, H. (1920). Studies in neurology. London: OxfordUniversity Press.

Landau, W., & Bishop, G. H. (1953). Pain from dermal,periosteal, and fascial endings and from inflammation.Archives of Neurology and Psychiatry, 69, 490–504.

Lewis, T., & Pochin, E. E. (1938). The double response ofthe human skin to a single stimulus. Clinical Science,3, 67–76.

F 1292 First and Second Pain Assessment

Noordenbos, W. (1959). Pain. Amsterdam: Elsevier.Price, D. D. (1972). Characteristics of second pain and

flexion reflexes indicative of prolonged centralsummation. Experimental Neurology, 37, 371–387.

Price, D. D. (1999). Psychological mechanisms of painand analgesia (p. 250). Seattle: IASP Press.

Price, D. D., Hu, J. W., Dubner, R., & Gracely, R. (1977).Peripheral suppression of first pain and central sum-mation of second pain evoked by noxious heat pulses.Pain, 3, 57–68.

Price, D. D., Frenk, H., Mao, J., & Mayer, D. J. (1994).The NMDA receptor antagonist dextromethorphanselectively reduces temporal summation of secondpain. Pain, 59, 165–174.

Thompson, S. W. N., & Woolf, C. J. (1990). Primaryafferent-evoked prolonged potentials in the spinalcord and their central summation: Role of the NMDAreceptor. In: M. R. Bond, J. Carlton, & C. J. Woolf(Eds.), Proceedings of the VIth World Congress onpain (pp. 291–298). Amsterdam: Elsevier.

Tommerdahl, M., Delemos, K. A., Vierck, C. J.,Favorov, O. V., & Whitsel, B. L. (1996). Anteriorparietal cortical response to tactile and skin heatingstimulation. Journal of Neurophysiology, 75(6),2662–2670.

Zotterman, Y. (1933). Studies in the peripheral nervousmechanisms of pain. Acta Medica Scandinavica, 80,185–242.

First Pain

Definition

First pain is a rapid onset, sharp, pricking nox-ious sensation that is associated with the activa-

tion of Ad nociceptors. When a noxious stimulus

is sufficient to activate both Ad andC nociceptors, first pain is perceived before sec-

ond pain due to differences in nerve conduction

velocity.

Cross-References

▶Encoding of Noxious Information in the Spinal

Cord▶ First and Second Pain Assessment (First Pain,

Pricking Pain, Pin-Prick Pain, Second Pain,

Burning Pain)▶Opioids, Effects of Systemic Morphine on

Evoked Pain

First Pain Assessment

▶ First and Second Pain Assessment (First Pain,Pricking Pain, Pin-Prick Pain, Second Pain,

Burning Pain)

First-Generation Antidepressants

▶Antidepressant Analgesics in PainManagement

First-Order Sensory Neurons

▶Opioid Modulation of Nociceptive Afferents

In Vivo

First-Order Subtype: MedialThalamotomy

▶Thalamotomy for Human Pain Relief

First-Pass Metabolism

Definition

The first-pass metabolism describes the transfor-

mation of the active drug after absorptionprior to reaching the systemic circulation,

i.e., pre-systemic elimination of the drug. It

mainly occurs after oral or deep rectal adminis-tration and can be avoided by intravenous, intra-

muscular, sublingual, buccal, or topical

administration.

Cross-References

▶NSAIDs, Pharmacokinetics

First-Pass Metabolism 1293 F

F

Fitness Training

▶ Physical Exercise

Fits of Pain

▶ Pain Paroxysms

Flare

▶Nociceptor, Axonal Branching

Flare, Flare Response

Definition

See also “neurogenic inflammation” and “axon

reflex.” Since the flare response is dependent on

the extension of the terminal arborization of theC-fibers mediating this axon reflex response,

i.e., their receptive fields, flare sizes vary in

different species and depend also on the typeof nerve fibers involved. Rodents do not show

a visible flare response since the receptive fields

of their C-afferents are small. They produce,however, a neurogenic plasma extravasation

upon the stimulation of C-fibers. In humans,

the flare responses following histamine stimu-lation are particularly large due to the large

receptive fields of the histamine-sensitive

C-fibers.

Cross-References

▶Nociceptor, Axonal Branching

▶ Polymodal Nociceptors, Heat Transduction▶Quantitative Thermal Sensory Testing of

Inflamed Skin

Flexion Exercise

▶Exercise

Flexion Withdrawal Reflex

Definition

This is a protective reflex usually elicited in the

lower limb and was originally described byCharles Sherrington as “the withdrawal of a limb

from an offending stimulus.” As originally char-

acterized, it involved the activation of flexor mus-cles via a group of afferent nerve fibers called

“flexor reflex afferents” with corresponding inhi-

bition of extensor muscles. However, more recentresearch has revealed that the flexion withdrawal

reflex has a more complex modular organization,

its activation being contingent upon the area ofskin being stimulated. Nevertheless, in the adult,

the nociceptive (i.e., produced by noxious stimuli)

flexion withdrawal reflex has proved invaluable asa model of nociceptive processing, and shows

a clear correlation with pain perception in terms

of threshold, peak intensity, and sensitivity toanalgesics. However, in the newborn infant, the

flexion withdrawal reflex can also be evoked withlow-intensity mechanical stimuli to the foot, such

as calibrated monofilaments (also called von Frey

hairs), and has a much lower threshold than thenociceptive flexion withdrawal reflex in the adult.

Cross-References

▶ Infant Pain Mechanisms

Flinching

Definition

At its most vigorous, flinching of the paw and/or

hindquarters is paw shaking, and when less

F 1294 Fitness Training

vigorous, rapid paw lifting. It is usually seen asdrawing the paw under the body and rapidly

vibrating it, and this causes a shudder or ripplingmotion across the back which is easy to observe

even when the paw is not visible. Each episode is

recorded as a single flinch.

Cross-References

▶ Formalin Test

Flip-Flop Isoform of AMPA Receptors

Definition

AMPA receptors have four subunits named

GluR1-4 (or GluRA-D), respectively. Each

subunit of the AMPA receptor exists in twoisoforms, so-called flip and flop due to alternative

splicing of a 115-base pair region encoding 38

amino acid residues immediately preceding thepredicted fourth membrane domain. The flip and

flop isoforms of AMPA receptors may be

differentially involved in pain transmission andresponse to injury.

Cross-References

▶Descending Circuitry, Molecular Mechanismsof Activity-Dependent Plasticity

Flunarizine

Definition

Calcium channel, dopamine, and histamine antag-onist used in the preventive treatment of migraine.

Cross-References

▶Headache Due to Arteritis

Fluorocitrate

Definition

Fluorocitrate blocks the activation of glial cells,

without directly affecting neurons, and functionsto inhibit the activity of aconitase, an enzyme

in the Krebs cycle of glia, but not neurons.

Peri-spinal administration of fluorocitrate blocksexaggerated pain.

Cross-References

▶Cord Glial Activation

Flurbiprofen

Definition

Flurbiprofen is a nonsteroid anti-inflammatory

drug (NSAID), which inhibits the formation ofprostaglandins by cyclooxygenase. It is selective

for COX-1, thus inhibits COX-1 at lower concen-

trations than COX-2.

Cross-References

▶Cyclooxygenases in Biology and Disease

fMRI

▶ Functional Magnetic Resonance Imaging

fMRI Imaging and PET in ParietalCortex

▶ PET and fMRI Imaging in Parietal Cortex

(SI, SII, Inferior Parietal Cortex BA40)

fMRI Imaging and PET in Parietal Cortex 1295 F

F

FMS

▶Muscle Pain, Fibromyalgia Syndrome(Primary, Secondary)

Focal Pain

Definition

Focal pain is that which is experienced at one site,superficial to the underlying nociceptive lesion.

Cross-References

▶Cancer Pain, Goals of a ComprehensiveAssessment

Focused Analgesia

Definition

Focused analgesia is based on increased anddirected attention to that part of the body for

which suggestions of analgesia have been given.

For example, suggestions for numbness in thehand may produce the experience of numbness

as well as reduced pain sensation.

Cross-References

▶Hypnotic Analgesia

Follicular Phase

Definition

The follicular phase is the time during which

a single dominant ovarian follicle develops. The

follicle should be mature at mid-cycle for

ovulation. The average length of this phase isabout 10–14 days. Variability in the length of

this phase is responsible for variations in totalcycle length.

Cross-References

▶ Premenstrual Syndrome

Forced-Choice Procedure

Definition

Forced-choice procedure is a statistical deci-

sion theory method in which a sensory deci-sion is made after two or more stimulus

presentations.

Forearm Ischemia Procedure

▶Tourniquet Test

Forearm Occlusion Pain

▶Tourniquet Test

Forebrain

Definition

Forebrain is the part of the brain including

the cerebral cortex, limbic system, and

hypothalamus.

Cross-References

▶ Forebrain Modulation of the Periaqueductal

Gray and Its Role in Pain

F 1296 FMS

Forebrain Modulation of thePeriaqueductal Gray and Its Rolein Pain

Dayna R. Loyd1 and Anne Z. Murphy2

1US Army Institute of Surgical Research,Fort Sam Houston, TX, USA2Neuroscience Institute, Georgia State

University, Atlanta, GA, USA

Introduction

Forebrain Inputs to PAGIn the 1980s and 1990s, tract-tracing studies froma number of laboratories (e.g., Beitz 1982;

Shipley et al. 1991) revealed an important feature

of the PAG; afferent inputs to the PAG arise froma staggering number of cortical and subcortical

forebrain sites. These inputs to the PAG are much

heavier than previously suspected and terminatewith a remarkable degree of topographic

specificity. Major identified forebrain afferents

to the PAG include the medial prefrontal cortex(MPF), the medial preoptic area (MPO), the

central and medial nuclei of the amygdala

(CeA, MeA), the ventromedial hypothalamus(VMH), and the paraventricular nucleus of the

hypothalamus (PVN).

Definition

The midbrain ▶ periaqueductal gray (PAG) and

its descending projections to the▶ rostral ventro-medial medulla (RVM) comprise a critical

descending neuroanatomical pathway modulat-

ing pain and analgesia. The PAG projects heavilyand directly to the RVM, which in turn projects to

the ▶ dorsal horn of the spinal cord. Both pain

and analgesia are modulated by emotional,motivational, and cognitive factors indicating

higher-order cortical and subcortical ▶ forebrain

modulation of the PAG-RVM-spinal cordpathway. Anatomical studies have demonstrated

that the PAG predominantly receives afferents

from the forebrain, including cortical and

subcortical sites involved in nociception. Theseforebrain projections terminate with a high

degree of topographical specificity within thePAG, forming longitudinal input columns

extending throughout the rostrocaudal extent of

the PAG and activating output neurons projectingto the RVM. Major identified forebrain afferents

to the PAG include the medial prefrontal cortex

(MPF), the medial preoptic area (MPO), thecentral and medial nuclei of the ▶ amygdala

(CeA, MeA), the ventromedial ▶ hypothalamus

(VMH), and the paraventricular nucleus of thehypothalamus (PVN).

Characteristics

Medial Prefrontal Cortex (MPF)The PAG receives dense inputs from large

groups of neurons in the orbital, medial pre-

frontal, and lateral (insular and perirhinal) cor-tices (Beitz 1982; Shipley et al. 1991; Floyd

et al. 2000). In total, inputs to the PAG arise

from at least 8 distinct cytoarchitectonic fieldsin the medial prefrontal and lateral cortices

(Shipley et al. 1991). ▶Retrograde tracing

demonstrates that projections to the PAG fromthe cerebral cortex arise from all fields of the

medial prefrontal cortex infralimbic, prelimbic,

anterior cingulate, and precentral medialis.Equally extensive projections arise from the

lateral suprarhinal (insular cortex) and

perirhinal cortical areas. Anterograde tracingreveals that the pattern of terminal labeling

from each medial or lateral cortical field is

highly organized and selectively targets dis-crete, columnar subregions of the PAG along

its entire rostrocaudal axis. Inputs from differ-

ent cortical fields terminate as different, largelycomplementary, longitudinal columns. Imag-

ing studies in humans have shown that anterior

cingulate and insular orbital cortices are con-sistently activated by the sensory-perceptual

and affective (i.e., emotional or unpleasant)

aspects of pain (Price 2000; Rolls et al. 2003).Analgesia, including opiate receptor-

dependent analgesia, can be elicited from the

anterior cingulate and insular cortices (see

Forebrain Modulation of the Periaqueductal Gray and Its Role in Pain 1297 F

F

Shipley et al. 1991; Burkey et al. 1996), and

both areas are activated in humans followingopioid or placebo treatment (Petrovic et al.

2002).

Central and Medial Nuclei of the Amygdala(CeA, MeA)Projections from the amygdala to the PAG arisepredominantly from the central and medial nuclei

of the CeA. The CeA projects in a columnar

manner to the PAG (Shipley et al. 1991).Additionally, a substantial population of PAG

neurons project to the CeA. The CeA projection

terminates as rostrocaudally oriented inputcolumns that focally target different

PAG subdivisions. The dorsomedial and lateral/

ventrolateral subdivisions are especially heavilytargeted (Shipley et al. 1991). Retrograde

tract-tracing from the lateral/ventrolateral PAG

reveals a dense population of projection neuronsin the CeA of both male and female rats,

and these projection neurons are activated by

24 h of hindpaw inflammation, observed ascolocalization with Fos as a measure of neural

activity (Fig. 1). There is also a dense projection

of neurons from the MeA to the lateral/ventrolat-eral PAG that are also active during inflammatory

pain (Fig. 2). The CeA is a key component ofcircuits involved in defense reactions, as well as

the mediation of both conditioned and innate

fear-related responses. In this regard, it isnoteworthy that conditioned and unconditioned

fear and aversive responses are accompanied by

antinociception (Helmstetter and Tershner 1994).Stimulation of the CeA produces analgesia

(Shipley et al. 1991; Oliveira and Prado 2001),

and the CeA is involved in analgesia elicited bysystemically administered opiates (Manning and

Mayer 1995). It is reasonable to speculate, there-

fore, that CeA projections to the PAG may medi-ate antinociceptive responses that accompany

fear and aversive responses. In agreement with

this hypothesis, lesions of the PAG and RVMattenuate analgesia associated with aversive

conditioned responses (Helmstetter and

Tershner 1994), and PAG lesions blockCeA-stimulation-produced analgesia (Oliveira

and Prado 2001).

Medial Preoptic Area (MPO)The MPO-PAG projection is very dense and

exhibits columnar organization, similar to theCeA-PAG projection. This projection arises

from neurons in several cytoarchitectonically

distinct subdivisions of the MPO, including thesexually dimorphic medial preoptic nucleus

(Fig. 3). These neurons are also activated follow-ing 24 h of inflammation in the rat hindpaw.

Forebrain Modulation ofthe Periaqueductal Grayand Its Role in Pain,Fig. 1 Photomicrographillustrating projectionneurons in the CeA of thefemale rat as identified byretrograde tracing from thelateral/ventrolateral PAGand observed as a brownprecipitate followingimmunohistochemicalprocessing. Also shown isFos expression to identifyneural activity in CeAneurons and CeA-PAGprojection neurons,observed as a blackprecipitate, following24 h of hindpawinflammation

F 1298 Forebrain Modulation of the Periaqueductal Gray and Its Role in Pain

Injections of anterograde tracers into the MPO

label dense, highly organized, and topographi-cally specific projections to the PAG.

A hallmark of this projection, like other forebrain

inputs studied to date, is that it forms longitudi-nally organized input columns that selectively

target discrete subregions of the PAG (i.e., thedorsomedial and lateral/ventrolateral PAG) along

its rostrocaudal axis. In particular, MPO inputs to

the PAG selectively terminate within the lateral/ventrolateral caudal PAG, where output neurons

to the RVM are selectively located (Murphy and

Hoffman 2001). Activation of the MPO bya variety of physiological factors also activates

longitudinally organized columns of PAGneurons, including those that project to the

Forebrain Modulation ofthe Periaqueductal Grayand Its Role in Pain,Fig. 3 Photomicrographillustrating MPO-PAGprojection neurons in thefemale rat labeled byretrograde tract-tracingfrom the lateral/ventrolateral PAG andobserved as brownprecipitate followingimmunohistochemistry.Also shown areFos-positive MPO neuronsand MPO-PAG projectionneurons indicating neuralactivity following 24 h ofinflammation in the rathindpaw (observed as blackprecipitate)

Forebrain Modulation ofthe Periaqueductal Grayand Its Role in Pain,Fig. 2 Photomicrographillustrating projectionneurons in the MeA of thefemale rat as identified byretrograde tracing from thelateral/ventrolateral PAGand observed as a brownprecipitate followingimmunohistochemicalprocessing. Also shown isFos expression to identifyneural activity in MeAneurons and MeA-PAGprojection neurons, observedas a black precipitate,following 24 h of hindpawinflammation

Forebrain Modulation of the Periaqueductal Gray and Its Role in Pain 1299 F

F

ventral medulla (Murphy and Hoffman 2001;

Normandin and Murphy 2008). The MPO is sex-ually dimorphic and plays a key role in neuroen-

docrine and steroidal regulation and maternal/

reproductive behaviors. Nociceptive thresholdsshift across the estrus cycle, with steroid hormone

administration and during reproductive activities

(see ▶ Sex Differences in Descending PainModulatory Pathways). Both the MPO and the

PAG contain high levels of estrogen and andro-

gen receptors (Murphy and Hoffman 2001; Loydand Murphy 2008). The MPO-PAG projection

neurons also coexpress the estrogen receptor

ERa (Fig. 4). In this regard, it is interesting tonote that there are sex differences in pain thresh-

olds as well as sex differences in how inflamma-

tory pain activates the PAG-RVM circuit (Loydand Murphy 2006). Furthermore, the PAG-RVM

pathway is anatomically and functionally sexu-

ally dimorphic (Loyd and Murphy 2006) and isessential for the observed sexual dimorphism in

morphine analgesia (Loyd et al. 2008). TheMPO,

therefore, may provide a key link mediating hor-monal influences on nociceptive thresholds and

may also regulate descending nociception during

maternal/reproductive behaviors (Murphy et al.1999). Consistent with this hypothesis, stimula-

tion of the MPO activates PAG neurons thatproject to the RVM (Rizvi et al. 1996), inhibits

dorsal horn spinal cord neuronal responses to

nociceptive stimuli, and also elicits analgesia(see Shipley et al. 1991; Zhang and Ennis 2005).

Hypothalamic Projections to the PAGThere is also evidence of various hypothalamic

nuclei projections to the lateral/ventrolateral

PAG as observed by retrograde tract-tracing,including the ventromedial hypothalamus

(VMH; Fig. 5) and the paraventricular nucleus

of the hypothalamus (PVN; Fig. 6). These hypo-thalamic nuclei are known to modulate fear and

stress responses, as well as sex and satiety behav-

iors. Hypothalamic projections to the PAG likelyplay a role in modulating these behavioral

responses during pain and analgesia; however,

little research has addressed these possibilities.Future research is warranted based on known

anatomical connectivity between the hypothala-

mus and the descending pain inhibitory system.

PAG-Forebrain Afferents Coordinatea Multitude of Behavioral ResponsesThere has been a growing recognition that the

PAG itself is far more complex than initially

suspected and is clearly involved in many morephysiological functions than nociception. For

example, stimulation of different columnarlyorganized regions of the PAG produces

Forebrain Modulation ofthe Periaqueductal Grayand Its Role in Pain,Fig. 4 Photomicrographillustrating MPO-PAGprojection neuronsidentified by retrogradetracing from the lateral/ventrolateral PAG andobserved as brownprecipitate followingimmunohistochemistry.Also shown is ERa-positiveMPO neurons andcolocalization with MPO-PAG neurons observed asblack precipitate

F 1300 Forebrain Modulation of the Periaqueductal Gray and Its Role in Pain

a number of distinctly different behavioral and

physiological responses including vocalization,autonomic changes, sexual/reproductive

behaviors, and fear and rage reactions (for review

see Shipley et al. 1991; Murphy et al. 1994;Murphy and Hoffman 2001; Loyd and Murphy

2009, Loyd and Murphy 2008). Not surprisingly,

many of the forebrain sites that project to thePAG are also known to regulate similar func-

tions. Based on these findings, a more integrativeconceptual framework has been adopted guided

by the working hypothesis that the PAG is

a structure that plays a central role in the produc-tion of certain stereotypical behaviors (e.g.,

reproduction, defense reactions, vocalization)

essential to the animal’s survival (Loyd and Mur-phy 2009). These behaviors require rapid, pro-

found autonomic adjustments and

simultaneously, significant alterations in painthresholds. From this perspective, it is reasonable

to consider that more highly elaborated forebrainstructures interact with the PAG to coordinate

Forebrain Modulation ofthe Periaqueductal Grayand Its Role in Pain,Fig. 6 Photomicrographillustrating PVN-PAGprojection neurons in thefemale rat identified byretrograde tract-tracingfrom the lateral/ventrolateral PAG andobserved as brownprecipitate followingimmunohistochemistry.Also shown areFos-positive PVN neuronsand PVN-PAG outputneurons indicating neuralactivity following 24 h ofhindpaw inflammation

Forebrain Modulation ofthe Periaqueductal Grayand Its Role in Pain,Fig. 5 Photomicrographillustrating VMH-PAGprojection neurons in thefemale rat identified byretrograde tract-tracingfrom the lateral/ventrolateral PAG andobserved as brownprecipitate followingimmunohistochemistry.Also shown are Fos-positive VMH neurons andVMH-PAG output neuronsindicating neural activityfollowing 24 h of hindpawinflammation

Forebrain Modulation of the Periaqueductal Gray and Its Role in Pain 1301 F

F

antinociceptive, behavioral, and autonomicresponses in concert with the dominant role of

the forebrain in cognitive and emotionalprocessing. Descending PAG output neurons

also exhibit columnar organization, such that

different output columns terminate with medialto lateral specificity in the ventral medulla in sites

involved in nociception, autonomic responses,

sexual/reproductive behaviors, and vocalization(Murphy and Hoffman 2001; Murphy et al. 1999;

Loyd and Murphy 2008, Loyd and Murphy 2009,

Loyd and Murphy 2006). Taken together, thesefindings suggest that forebrain sites may trigger

or modulate specific nociceptive and autonomic

adjustments via activation of discrete columns ofPAG output neurons.

Summary

The PAG and the RVM are major nodes for

bidirectional modulation of nociception and spi-

nal cord neuronal responses to noxious sensoryinput. The PAG-RVM circuit is demonstrably

central to analgesia elicited by activation of

endogenous opioidergic systems as well as thatresulting from exogenously administered opi-

oids. Nociceptive regulation is but one aspect of

this circuit as the PAG is clearly a highly orga-nized structure that integrates defensive, fear/

anxiety, and hormonal/reproductive behaviors in

discrete columns that extend longitudinallythrough the structure. These columns receive

dense and topographically specific input from

cortical and subcortical forebrain areas centrallyinvolved in these same functions. Some forebrain

areas also project in parallel to the RVM, and the

functional significance of such dual projections isnot known. In humans, whose behavior is domi-

nated by the massive and highly elaborated fore-brain, the projections to the PAG and RVM are

likely to regulate nociception in concert with

forebrain-mediated cognitive and emotionalprocessing of pain and its perceived impact.

Acknowledgement The authors would like to recognizethe contributions of Dr. Matthew Ennis and Xijing Zhangon the first edition of this chapter.

References

Beitz, A. J. (1982). The organization of afferent projec-tions to the periaqueductal gray of the rat. Neurosci-ence, 7, 133–159.

Burkey, A. R., Carstens, E., Wenniger, J. J., et al. (1996).An opioidergic cortical antinociception triggering sitein the agranular insular cortex of the rat contributes tomorphine antinociception. The Journal of Neurosci-ence, 16, 6612–6623.

Floyd, N. S., Price, J. L., Ferry, A. T., et al. (2000).Orbitomedial prefrontal cortical projections todistinct longitudinal columns of the periaqueductalgray in the rat. The Journal of Comparative Neurology,422, 556–578.

Helmstetter, F. J., & Tershner, S. A. (1994). Lesions of theperiaqueductal gray and rostral ventromedial medulladisrupt antinociceptive but not cardiovascular aversiveconditional responses. The Journal of Neuroscience,14, 3099–7108.

Loyd, D. R., & Murphy, A. Z. (2006). Sex differences inthe anatomical and functional organization of theperiaqueductal gray-rostral ventromedial medullarypathway in the rat: A potential circuit mediating thesexually dimorphic actions of morphine. The Journalof Comparative Neurology, 496, 723–738.

Loyd, D. R., & Murphy, A. Z. (2008). Androgen andestrogen (a) receptor localization on periaqueductalgray neurons projecting to the rostral ventromedialmedulla in the male and female rat. Journal ofChemical Neuroanatomy, 36, 216–226.

Loyd, D. R., & Murphy, A. Z. (2009). The role of theperiaqueductal gray in the modulation of pain in malesand females: are the anatomy and physiology really thatdifferent? Neural Plast. doi: 10.1155/2009/462879.

Loyd, D. R., Wang, X., & Murphy, A. Z. (2008). Sexdifferences in mu opioid receptor expression in therat midbrain periaqueductal gray are essential foreliciting sex differences in morphine analgesia. TheJournal of Neuroscience, 28(52), 14007–14017.

Manning, B. H., & Mayer, D. J. (1995). The centralnucleus of the amygdala contributes to the productionof morphine antinociception in the rat tail flick test.The Journal of Neuroscience, 15, 8199–8213.

Murphy, A. Z., Ennis, M., Shipley, M. T., & Behbehani,M.M. (1994). Directionally specific changes in arterialpressure induce differential patterns of fos expressionin discrete areas of the rat brainstem: a double-labelingstudy for Fos and catecholamines. The Journal ofComparative Neurology, 349(1), 36–50.

Murphy, A. Z., Rizvi, T. A., Ennis, M., et al. (1999). Theorganization of preoptic-medullary circuits in themale rat: Evidence for interconnectivity of neuralstructures involved in reproductive behavior,antinociception and cardiovascular regulation. Neuro-science, 91, 1103–1116.

Murphy, A. Z., & Hoffman, G. E. (2001). Distribution ofgonadal steroid receptor-containing neurons in thepreoptic-periaqueductal gray-brainstem pathway: a

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potential circuit for the initiation of male sexual behav-ior. The Journal of Comparative Neurology, 438(2),191–212.

Normandin, J. J., & Murphy, A. Z. (2008). Nucleusparagigantocellularis afferents in male and femalerats: organization, gonadal steroid receptor expression,and activation during sexual behavior. The Journal ofComparative Neurology, 508(5), 771–794.

Oliveira, M. A., & Prado,W. A. (2001). Role of the PAG inthe antinociception evoked from the medial or centralamygdala in rats. Brain Research Bulletin, 54, 55–63.

Petrovic, P., Kalso, E., Petersson, K. M., et al. (2002).Placebo and opioid analgesia-imaging a shared neuro-nal network. Science, 295, 1737–1740.

Price, D. D. (2000). Psychological and neural mechanismsof the affective dimension of pain. Science, 288,1769–1772.

Rizvi, T. A., Ennis,M.,Murphy, A. Z., et al. (1996). Medialpreoptic afferents to periaqueductal gray medullo-output neurons: A combined Fos and tract tracingstudy. The Journal of Neuroscience, 16, 333–344.

Rolls, E. T., O’Doherty, J., Kringelbach, M. L., et al.(2003). Representations of pleasant and painful touchin the human orbitofrontal and cingulate cortices.Cerebral Cortex, 13, 308–317.

Shipley, M. T., Ennis, M., Rizvi, T. A., et al. (1991).Topographical specificity of forebrain inputs to themidbrain periaqueductal gray: Evidence for discretelongitudinally organized input columns. In A. Depaulis& R. Bandler (Eds.), The midbrain periaqueductal graymatter (pp. 417–448). New York: Plenum Press.

Zhang, Y. H., & Ennis, M. (2007). Inactivation ofthe periaqueductal gray attenuates antinociceptionelicited by stimulation of the rat medial preoptic area.Neurosci Lett. 429(2–3), 105–110.

Formalin Test

Terence J. Coderre1, Frances V. Abbott2 andJana Sawynok3

1Departments of Anesthesia, Neurology &

Neurosurgery and Psychology, McGillUniversity, Montreal, QC, Canada2Departments of Psychiatry and Psychology,

McGill University, Montreal, QC, Canada3Department of Pharmacology, Dalhousie

University, Halifax, Canada

Synonyms

Nociception induced by injection of dilute

formaldehyde

Definition

The formalin test refers to the quantification of

characteristic nociceptive behaviors that occur inresponse to subcutaneous (s.c.) or intradermal

injection of a dilute solution of formaldehyde in

0.9 % saline, typically into the dorsal or plantarhindpaw of rodents.

Characteristics

The formalin test was originally described byDubuisson and Dennis (1977) using 50 ml of

5 % formalin injected s.c. into the dorsal surface

of one forepaw in rats and cats. “Five percentformalin” consisted of 1 ml of saturated formal-

dehyde (37 %) in water + 19 ml 0.9 % saline

(i.e., 1.85 % formaldehyde). It is now more com-mon to inject between 0.2 % and 5 % formalin

into the dorsal or plantar hindpaw, using 20–50 mlin rats or 10–25 ml in mice. Another common siteis the lateral aspect of the muzzle, or the tempo-

romandibular joint, in rats, as a model of

orofacial pain (Clavelou et al. 1995). Thehindpaw has replaced the forepaw as a preferred

site, because rats and mice frequently lick the

forepaw in normal grooming. The formalin testhas also been used in other species, including

guinea pigs, rabbits, primates, crocodiles, domes-

tic fowl, and octodon degus (Tjølsen et al. 1992).Nociceptive behaviors increase with formalin

concentration in rats and mice but reach a plateau

between 2 % and 5 % formalin regardless of thescoring method used (see below) (Tjølsen et al.

1992; Coderre et al. 1993; Abbott et al. 1995;

Sawynok and Liu 2003). With further increasesin concentration, the magnitude and duration of

the behavioral response are not increased; rather

the animal’s behavior becomes more disorga-nized, and the nociceptive scores may actually

fall. Formalin concentrations of 1 % or less areuseful for detecting the actions of weak analge-

sics, avoiding ceiling effects (Abbott et al. 1995;

Sawynok and Liu 2003).Factors that influence the magnitude of the

response include the site of injection (plantar

injections produce greater responses), age of the

Formalin Test 1303 F

F

animal (responses are greater in infant rats),

the strain, the degree to which the animal is

habituated to handling, and the testing environ-ment (unfamiliar environments can produce

stress-induced analgesia), level of morbidity

(e.g., time since surgery), and temperature ofthe animal colony and the testing environment

(heat increases peripheral blood flow and the

inflammatory response). Other environmentalfactors, such as sounds, odors, light, atmospheric

pressure, or even activity of humans in the test

room, can also influence the expression of noci-ceptive behaviors. Formalin concentrations

should be decided on the basis of the scientificobjectives of the study, with adjustments for the

response of animals under the conditions

prevailing at the laboratory (Tjølsen et al. 1992;

Sawynok and Liu 2003). For ethical reasons, thelowest possible concentration of formalin consis-

tent with scientific objectives should be used.

Dubuisson and Dennis (1977) quantified for-malin nociception using a ▶weighted-scores

technique (WST), which involves assigning

weights to each behavioral category measured(paw favoring, paw elevation, or licking, biting,

or shaking of the paw) (Figs. 1, 2a). The

ordinality and validity of the category weightsin the WST have been well established in rats

(Coderre et al. 1993; Abbott et al. 1995). Othershave used single behavioral scoring methods,

Formalin Test, Fig. 1 Behavioral categories used in theweighted-scores technique of formalin test scoringdevised by Dubuisson and Dennis (1977), illustratedfor hindpaw injections (0 injected paw is not favored,

1 injected paw has little or no weight on it, 2 injectedpaw is elevated and not in contact with any surface,3 injected paw is licked, bitten, or shaken)

2.0a b

Control

Pai

n In

tens

ity R

atin

g

Mea

n N

o. o

f Flin

ches

Morphine

Weighed Scores Technigue Flinching or Licking

1.5

1.0

0.5

0.010 20

Time (min) Time (min)

30 40 50 60 0

40

30

20

10

0

10 20 30 40 50 60 70 80

80

60

40

Mean Licking T

ime (sec)

20

0

Formalin Test, Fig. 2 Time course of nociceptiveresponses after injection of 5 % formalin in rats. (a) Painintensity ratings using the weighted-scores technique. (b)Number of flinches (closed squares) and time spent

licking (closed circles). Note that all three measures illus-trate the biphasic nature of nociceptive responses(Modified with permission from (a) Dubuisson andDennis (1977) and (b) Wheeler-Aceto and Cowan (1991))

F 1304 Formalin Test

including recording of the time spent licking/bit-ing the injected paw (Hunskaar et al. 1985) or

counting the number of flinches (Wheeler-Acetoand Cowan 1991) (Fig. 2b), or have used auto-

mated scoring techniques (Jourdan et al. 2001).

Parametric analysis suggests that the WST issuperior to any single nociceptive measure; how-

ever, it is clear that assessment of paw favoring

adds little to the equation and may be omittedfrom the analysis (Abbott et al. 1995). Paw lick-

ing/biting scores are commonly used in the

mouse formalin test, since these behaviors pre-dominate in mice and are easily quantified. It has

been argued that ▶ flinching is more robust and

less influenced by treatments affecting otherbehaviors (e.g., motor function), while licking/

biting is regarded as being more variable and

subject to motor influences, stereotypy, and per-haps taste aversion following earlier licking epi-

sodes (Wheeler-Aceto and Cowan 1991).

Flinching and licking/biting may reflect distinctneuronal mechanisms, as they can be differen-

tially modulated by certain drugs and procedures

(e.g., amitriptyline and naloxone decrease lick-ing/biting behaviors while simultaneously

increasing flinching behaviors) (Sawynok and

Liu 2003).Concerning validation, the formalin concen-

tration-response relationship, and the analgesic

effects of opioids, has been examined for mostscoring methods. However, few studies have

determined whether nociceptive scores are

suppressed by drugs known not to be analgesicin humans. The latter is particularly important,

because sedation and other toxic effects can

appear as analgesia. When different behaviorscompete (e.g., a rat cannot favor its paw at the

same time as licking it), then the interpretation of

the change depends on whether one behaviorrepresents greater nociception than another.

This is problematic for some scoring methods,

because a decrease in a behavior considered torepresent greater nociception may occur because

of drug side effects (Abbott et al. 1995). On the

other hand, the selection of scoring method mayalso depend on other factors, such as the drug

administration method. For example, in some

cases, the presence of a chronic intrathecal (I.T.)

cannula can eliminate the expression of licking/biting behaviors, yet leave flinching unaltered.

This may be the reason why studies using ratsand chronic I.T. cannulas (PE-10 tubing) gener-

ally do not report licking/biting behaviors as an

outcome, yet when drugs are given spinally byacute lumbar puncture, such behaviors are often

reported (Sawynok and Reid 2003).

An important characteristic of the formalintest is that there are two distinct phases of noci-

ceptive behavior, described as the early and late,

or first and second, phases. The early phase lasts5–10 min; this is followed by a quiescent inter-

val of 5–10 min, and then a subsequent late

phase of activity is observed up to 60–90 min.The biphasic response to formalin is prominent

in rats and mice, regardless of the nociceptive

scoring method (i.e., WST, flinches, licking/bit-ing, or automated) (Fig. 2), but is less obvious in

other species (Tjølsen et al. 1992). The biphasic

nature of the formalin response is also observedfor heart rate and blood pressure (Taylor et al.

1995), as well as the neuronal activity of Ad- andC-fiber sensory afferent neurons (Puig andSorkin 1995) or deep dorsal horn neurons of

the spinal cord (Dickenson and Sullivan 1987)

(Fig. 3). The two phases of nociceptive activitylikely reflect an initial direct activation of noci-

ceptive primary afferents (i.e., nociceptors) by

formalin, followed by afferent activation pro-duced by inflammatory mediators released fol-

lowing tissue injury (Dubuisson and Dennis

1977; Tjølsen et al. 1992). The late phase mayalso involve ▶ central sensitization (Coderre

2001). A quiescent interval in C-fiber and dorsal

horn neuron activation (Puig and Sorkin 1995;Dickenson and Sullivan 1987) tends to support

the notion that distinct mechanisms underlie the

two phases of behavioral and electrophysiolog-ical activation. However, the “interphase” also

reflects ▶ active inhibition initiated by pro-

cesses activated in phase 1. For example,a second formalin injection, administered

20 min after the initial injection, produces inhi-

bition of behavioral responses and electrophys-iological activity, with a time frame that

corresponds to the first interphase interval

(Fig. 4) (Henry et al. 1999).

Formalin Test 1305 F

F

Electrophysiological and pharmacologicalstudies suggest that the early-phase formalin

response depends on both the direct activationof nociceptors and ▶ neurogenic inflammation

generated by the release of bradykinin,

5-hydroxytryptamine, histamine, and adeno-

sine triphosphate (Tjølsen et al. 1992;Sawynok and Liu 2003). Formalin might also

disrupt the perineurium, and this could

enhance the access of tissue mediators to thesensory nerve. The late-phase formalin

response depends in part on neurogenic inflam-

mation induced by the above mediators as wellas inflammatory responses associated with the

release of cytokines and breakdown of

arachidonic acid (Tjølsen et al. 1992; Sawynokand Liu 2003). There is also evidence to sug-

gest that substance P- and glutamate-mediated

central sensitization, initiated during the earlyphase, contributes to nociception in the late

phase of the formalin test. This evidence

arose from observations that the spinal admin-istration of local anesthetics, opioids, and sub-

stance P or glutamate (N-methyl-D-aspartate)

receptor antagonists inhibits late responseswhen given prior to, but not after, the early

phase (Dickenson and Sullivan 1987; Coderre

2001). These findings have prompted theextensive use of the formalin test as an animal

model for examining the potential of treat-

ments for producing ▶ preemptive analgesia.The mechanisms underlying the active inhibi-

tion during the interphase are not completelyunderstood but probably depend on both spinal

5

formalinC-Fiber Responsea b DH Neuron Response

formalin500

4

3

2

1

00 10 20 30

Time (min)40 50

400

Spi

kes/

sec

Spi

kes/

sec

300

200

100

00 10 20 30

Time (min)40 50 60

Formalin Test, Fig. 3 Time course of (a) mean C-fiberresponses in sural nerve and (b) an individual dorsal horn(DH) convergent neuron response to hindpaw formalininjections of 5 % formalin in rats. Note the biphasic nature

of neuronal responses in both C-fibers and DH neurons(Modified with permission from (a) Puig and Sorkin(1995) and (b) Dickenson and Sullivan (1987))

3

2

Noc

icep

tive

Sco

re

1

00 10 20 30 40

Time (min)

2.5% x 1 (0 min)2.5% x 2 (0 & 20 min)

50 60

Formalin Test, Fig. 4 Effects of one or two injections(20-min interinjection interval) of 2.5 % formalin into theplantar surface of one hindpaw on nociceptive scores inthe formalin test. Filled triangles show the typicalbiphasic nociceptive response to a single injection. Opentriangles show the effects of two injections of formalin.Note the second inhibitory interphase after the secondformalin injection in the group that had two injections(Modified with permission from Henry et al. (1999))

F 1306 Formalin Test

and supraspinal influences, since the inter-phase is still present in spinalized animals but

is eliminated by brain transection at the mes-encephalic-diencephalic junction. A role for

GABAA receptors is suggested because the

interphase is reduced both by spinal adminis-tration of GABAA receptor antagonists and by

systemic administration of low doses of barbi-

turates (Sawynok and Liu 2003).While release of inflammatory mediators con-

tributes to formalin-induced nociception, inflam-

mation alone is not sufficient to produce thenociceptive behaviors induced by formalin.

Thus, injection of inflammatory agents such as

yeast, carrageenan, or Complete Freund’s Adju-vant (CFA) into the hindpaw produces profound

edema but essentially no nociceptive shaking,

licking, or flinching behaviors as produced byformalin. This implies that activation of

nociceptors is a complex process that is to some

extent dissociable from inflammatory processes(Sawynok and Liu 2003). Importantly, the

inflammatory response to formalin, and the reli-

ance of nociceptive response on inflammation,depends significantly on the concentration and

volumes of formalin administered. Assuming

that injection volumes are similar, low concen-trations of formalin (1–2.5 % formalin or less)

produce very little ▶ plasma extravasation and

edema, while greater concentrations (5 %) pro-duce significant hindpaw inflammation, lasting

for as long as 1 week after injection. In addition,

studies using adult pretreatment with capsaicin(to desensitize TRPV1-expressing nociceptors)

and anti-inflammatory drugs (to target

▶ nonneurogenic inflammation) suggest thatlow concentrations of formalin produce effects

that depend on neurogenic inflammation,

whereas greater concentrations of formalindepend on nonneurogenic inflammation

(Sawynok and Liu 2003; Coderre 2001). With

greater concentrations of formalin, it is alsomore difficult to demonstrate a role for central

sensitization in the late phase. Thus, nociceptive

behaviors produced by 1–2.5 % formalin, but notthose produced by 3.75–5 % formalin, are

sensitive to preemptive effects of spinal adminis-

tration of local anesthetics (Coderre 2001). The

evidence suggesting differing roles of neurogenicand nonneurogenic inflammation with low and

high concentrations of formalin has been recog-nized in rats, but not mice. However, it should be

noted that the relatively large volumes of forma-

lin injections typically used in mice produce sig-nificant inflammation even at low concentrations

of formalin (reflecting different injection to tissue

volume ratios) and might not allow for sucha clear distinction.

Recent studies using knockout mice provide

further insights into molecular mechanismsinvolved in formalin activation of nociceptors.

In vitro data indicates that formaldehyde acti-

vates TRPA1 receptors, which is supported bycomplementary in vivo data that TRPA1-

deficient ($/$) mice exhibit markedly reduced

behavioral responses to formalin (Macphersonet al. 2007; McNamara et al. 2007). However,

the attenuation of nociceptive responses is seen

only at a low concentration of formalin(0.5 %), and there are no differences in

responses at greater concentrations of formalin

(2 % and 5 %) which are used more commonlyin nociceptive behavioral tests (Braz and

Basbaum 2010). At the lower concentration,

most formalin-responsive afferents are unmy-elinated, but greater concentrations recruit

both unmyelinated and myelinated afferents

(Braz and Basbaum 2010). The involvementof myelinated afferents in greater concentra-

tions of formalin-induced behaviors is further

supported by observations that ablation of thevast majority of C-fiber nociceptors does not

alter such responses (Shields et al. 2010).

Nerve injury occurs following administrationof formalin, even at 0.5 %, as all concentra-

tions of formalin lead to induction of activat-

ing transcription factor 3 (ATF3), a reliablemarker of nerve injury (Braz and Basbaum

2010). Hindpaw inflammation produced by

CFA did not induce ATF3, and carrageenanled to only a slight effect; these observations

suggest that nerve damage, not increased activ-

ity in nociceptors, resulted in ATF3 induction(Braz and Basbaum 2010).

Formalin injections also activate processes

that lead to long-term changes in the central

Formalin Test 1307 F

F

nervous system. Formalin injections lead tothe spinal activation of various intracellular

signaling molecules, such as cyclic-adenosinemonophosphate (cAMP), protein kinase C,

nitric oxide, cyclic-guanosine monophosphate

(cGMP), mitogen-activated protein kinase(MAPK), cAMP-response element binding

protein (CREB), as well as proto-oncogenes

and their protein products, including c-fos, c-jun, Krox-24, Fos, Jun B, and Jun D. Formalin

injections also produce delayed activation of

microglia in spinal cord dorsal horn. Thesechanges may underlie long-term changes in

mechanical and thermal sensitivity that occur

in sites adjacent to or remote from the injec-tion site, which last from days to weeks after

the injection (Sawynok and Liu 2003; Coderre

2001).

Cross-References

▶Behavioral Studies in Animals

▶Cingulate Cortex▶Nociceptive Processing in the Hippocampus

and Entorhinal Cortex, Neurophysiology and

Pharmacology

References

Abbott, F. V., Franklin, K. B. J., & Westbrook, R. F.(1995). The formalin test: Scoring properties of thefirst and second phases of the pain response in rats.Pain, 60, 91–102.

Braz, J. M., & Basbaum, A. I. (2010). Differential ATF3expression in dorsal root ganglion neurons reveals theprofile of primary afferents engaged by diverse chem-ical stimuli. Pain, 150, 290–301.

Clavelou, P., Dallel, R., Orliaguet, T., Woda, A., &Raboisson, P. (1995). The orofacial formalin test inrats: Effects of different formalin concentrations. Pain,62, 295–301.

Coderre, T. J. (2001). Noxious stimulus-induced plasticityin spinal cord dorsal horn: Evidence and insights onmechanisms obtained using the formalin test. In M. M.Patterson & J. W. Grau (Eds.), Spinal cord plasticity:Alterations in reflex function (pp. 163–183). Boston:Kluwer Academic.

Coderre, T. J., Fundytus, M. E., McKenna, J. E., Dalal, S.,& Melzack, R. (1993). The formalin test: A validation

of the weighted-scored method of behavioral painrating. Pain, 54, 43–50.

Dickenson, A. H., & Sullivan, A. F. (1987). Subcutane-ous formalin-induced activity of dorsal horn neuronesin the rat: Differential response to an intrathecal opi-oid administered pre or post formalin. Pain, 30,349–360.

Dubuisson, D., & Dennis, S. G. (1977). The formalin test:A quantitative study of the analgesic effects of mor-phine, meperidine, and brain stem stimulation in ratsand cats. Pain, 4, 161–174.

Henry, J. L., Yashpal, K., Pitcher, G. M., & Coderre, T. J.(1999). Physiological evidence that the “Interphase” inthe formalin test is due to active inhibition. Pain, 82,57–63.

Hunskaar, S., Fasmer, O. B., & Hole, K. (1985). Formalintest in mice, a useful technique for evaluating mildanalgesics. Journal of Neuroscience Methods, 14,69–76.

Jourdan, D., Ardid, D., & Eschalier, A. (2001). Automatedbehavioural analysis in animal pain studies. Pharma-cological Research, 43, 103–110.

Macpherson, L. J., Xiao, B., Kwan, K. Y., Petrus, M. J.,Dubin, A. E., Hwang, S. W., Cravatt, B., Corey, D. P.,& Patapoutian, A. (2007). An ion channel essential forsensing chemical damage. The Journal of Neurosci-ence, 27, 11412–11415.

McNamara, C. R., Mandel-Brehm, J., Bautista, D. M.,Siemens, J., Deranian, K. L., Zhao, M.,Hayward, N. J., Chong, J. A., Julius, D., Moran,M. M., & Fanger, C. M. (2007). TRPA1 mediatesformalin-induced pain. Proceedings of National Acad-emy of Sciences USA, 104, 13525–13530.

Puig, S., & Sorkin, L. S. (1995). Formalin-evoked activ-ity in identified primary afferent fibres: Systemiclidocaine suppresses phase-2 activity. Pain, 64,345–355.

Sawynok, J., & Liu, X. J. (2003). The formalin test:Characteristics and usefulness of the model. Reviewsin Analgesia, 7, 145–163.

Sawynok, J., & Reid, A. R. (2003). Chronic intrathecalcannulas inhibit some and potentiate other behaviorselicited by formalin injection. Pain, 103, 7–9.

Shields, S. D., Cavanaugh, D. J., Lee, H., Anderson,D. J., & Basbaum, A. I. (2010). Pain behavior in theformalin test persists after ablation of the greatmajority of C-fiber nociceptors. Pain, 151,422–429.

Taylor, B. K., Peterson, M. A., & Basbaum, A. I. (1995).Persistent cardiovascular and behavioral nociceptiveresponses to subcutaneous formalin require peripheralnerve input. The Journal of Neuroscience, 15,7575–7584.

Tjølsen, A., Berge, O. G., Hunskaar, S., Rosland, J. H., &Hole, K. (1992). The formalin test: An evaluation ofthe method. Pain, 51, 5–17.

Wheeler-Aceto, H., & Cowan, A. (1991). Standardizationof the rat paw formalin test for the evaluation ofanalgesics. Psychopharmacology, 104, 35–44.

F 1308 Formalin Test

Forty Hz Oscillations

Definition

40 Hz activity is oscillatory activity described in

the brain when the organism is actively engagedin a task.

Cross-References

▶Corticothalamic and ThalamocorticalInteractions

Fos Expression

Definition

The expression of Fos protein, the gene product

of the c-Fos gene. Fos expression in a particular

set of central nervous system neurons is oftentaken to indicate activity of that set of neurons

in response to a noxious stimulus.

Cross-References

▶Visceral Pain Model, Lower GastrointestinalTract Pain

Fos Protein

Definition

Fos is the protein that is expressed by the c-Fos

gene in nociceptive neurons after noxious stim-

ulation. Fos protein is found in the nucleus,where it serves as a transcription factor (third

messenger).

Cross-References

▶ c-fos

▶ Spinal Cord Injury Pain Model, ContusionInjury Model

▶ Spinal Dorsal Horn Pathways, Dorsal Column

(Visceral)▶ Spinothalamic Tract Neurons, Role of Nitric

Oxide

Fractalkine

Definition

Fractalkine is a cell-surface protein expressed by

neurons in the spinal cord. When sufficiently

activated, spinal neurons release fractalkine,which then binds to receptors expressed on

microglia, thereby inducing the release of the

proinflammatory cytokine interleukin (IL)-1.Peri-spinal administration of fractalkine, as well

as IL-1, induces exaggerated pain responses.

Importantly, inhibiting fractalkine activity blocksneuropathic pain, implying that endogenous

fractalkine generates enhanced pain responses.

Cross-References

▶Cord Glial Activation

Fractalkine (CX3CL1)

▶Cathepsin and Microglia

Free from Bias

Definition

A personal attitude that may influence the evalu-

ation of patients’ pain conditions or the

Free from Bias 1309 F

F

interpretation of study results. Pain measuresshould be bias-free in that children should use

them in the same manner regardless of differ-ences in how they wish to please adults.

Cross-References

▶ Pain Assessment in Children

Free Magnitude Estimation

Definition

Free magnitude estimation is the numerical ratingof sensation magnitude without upper or lower

boundaries.

Cross-References

▶Opioids, Effects of Systemic Morphine on

Evoked Pain

Free Nerve Endings

▶Non-corpuscular Sensory Endings

Freeze Lesion

Definition

A brief punctual freeze lesion of human skin that

causes moderate burning or itching sensationstogether with a reddening and a short-lived

edema, after 24 h hyperalgesia to punctuate stim-

uli, hyperalgesia to blunt pressure and impactstimuli, and increased heat sensitivity. Brush-

evoked hyperalgesia does not develop after

freezing.

Cross-References

▶ Freezing Model of Cutaneous Hyperalgesia

Freezing Model of CutaneousHyperalgesia

Susanne K. Sauer

Department of Physiology and Pathophysiology,University of Erlangen, Erlangen, Germany

Synonyms

Cold-induced hyperalgesia; Cutaneous freezetrauma; Cutaneous hyperalgesia; Inflammatory

hyperalgesia by skin freezing

Definition

A brief ▶ freeze lesion of human skin is a viable

model to induce a slowly developing and

sustained pattern of ▶ hyperalgesia. Duringfreezing, moderate burning or itching sensations

together with a reddening and a short-lived

edema of the lesioned skin site can be observed.No spontaneous pain or hyperalgesia arises dur-

ing the first hours after freezing the skin. About

24 h after induction, a typical pattern ofhyperalgesia develops: hyperalgesia to punctuate

stimuli, hyperalgesia to blunt pressure and

impact stimuli, and increased heat sensitivity.Brush-evoked hyperalgesia (▶ allodynia) does

not usually develop after freezing.

Characteristics

Injury of the skin is often followed by augmented

pain sensations to mechanical, thermal, or chem-ical stimuli. Since the mechanism of the induc-

tion and maintenance of the different types of

hyperalgesia are areas of considerable interest,scientists have searched for adequate experimen-

tal models, e.g., standardized lesions of the skin.

Freeze injury of the skin was first described by

F 1310 Free Magnitude Estimation

Lewis and Love in 1926 (Lewis and Love 1926),maybe stirred by reports from expeditions to the

North Pole in this decade, describing freeze inju-ries of their fingers and feet.

Experimental ProceduresExperimental inflammation by freezing the skin

is normally induced on the upper leg, the forearm,

or the back of the hand. For this purpose acylindrical copper bar with a standardized diam-

eter and weight (e.g., 15 mm and 290 g, respec-

tively) is cooled to – 28 #C (Kilo et al. 1994). Thisbar is placed on the skin, with its long axis

perpendicular to the surface and a contact pres-

sure provided by its weight. To improve thermalcontact to the skin, saline-soaked filter paper is

placed on the skin beneath the copper bar. The

degree of developing inflammation is determinedby the temperature of the copper bar and the

thawing time of the lesioned skin site. The dura-

tion of freezing assessed that thawing durationnormally account as to 20–40 s. Sensory testing

for different forms of hyperalgesia follows

22–24 h after freezing the skin.

Early Skin Reactions and Activation ofPrimary AfferentsVolunteer subjects describe freezing of the skin as

moderately painful, with sensations of electric

prickling or slight itching. Intense burning sensa-tions are reported rarely. At the lesioned skin site,

a sharply delineated region of local reddening

develops, due to both cold-induced vasodilatationand local edema which subside within 1–2 h

(Lewis and Love 1926; Kilo et al. 1994). Freezing

itself obviously provokes relatively little sponta-neous activity in superficial ▶ nociceptors

because they are rapidly inactivated by the

decrease in skin temperature. Before inactivationby freezing Ad and C-nociceptors respond to

noxious temperatures down to about $10 #C

with graded responses. Units are recruitedprogressively with decreasing temperature and

are thus suited to contribute to the sensation of

cold pain (Simone and Kajander, 1996; Simoneand Kajander, 1997; Campero et al. 1996)). The

obviously brief activation of nociceptors is

reflected by a very spatially limited region of

▶ neurogenic inflammation around the frozenskin, since no flare or wheal reaction can be

observed. For transduction of cold stimuli, differ-ent mechanisms have been proposed: activation

of transient receptor potential channels, namely,

▶TRPA1 and ▶TRPM8, or inhibition of back-ground potassium channels (Belmonte et al.,

2009; Foulkes and Wood, 2007). Further on also

a TTX-resistant sodium channel ▶NaV1.8,which does not inactivate while cooling, is par-

ticularly important to retain excitability while

cooling (Zimmermann et al., 2007).The destruction of the cells in the upper skin

layers evokes a complex inflammatory process,

responsible for the altered pain sensation devel-oping within the first day after freezing the skin.

Activation and Sensitization of NociceptiveSpinal Cord NeuronsNociceptive spinal dorsal horn neurons respond to

freeze injury of the skin. Both ▶wide dynamicrange (WDR) and ▶ nociceptive specific neurons

(NS) are stimulated when the skin temperature in

their innervation territories is lowered to $15 #C(Khasabov et al. 2001). WDR and NS neurons

respond with a high-frequency discharge at the

onset of freezing and subsequent ongoing activity.Moreover, a cross-sensitization by freezing of heat

and cold activation thresholds is observed.

Although little is known about the specific sub-types of peripheral afferents that excite the WDR

and NS neurons, it is known that both types of

dorsal horn neurons contribute to the cold and heathyperalgesia produced by freeze injury. In a rat

model, freezing the skin of the hindpaw also leads

to increased ▶ c-fos expression in the spinal cord(Abbadie et al. 1994; Doyle and Hunt 1999).

Heat HyperalgesiaHeat hyperalgesia, for instance, that following

▶ capsaicin application, is restricted to the pri-

mary hyperalgesic zone, and the underlyingmechanism responsible for this is a peripheral

sensitization of polymodal, mechano-heat sensi-

tive, mostly unmyelinated nociceptors (Treedeet al. 2004; Ali et al. 1996). Similarly heat

hyperalgesia is observed at the injured skin site

after freezing (1# zone) and to a minor extent also

Freezing Model of Cutaneous Hyperalgesia 1311 F

F

in the 2# zone. The peripheral sensitization ofheat sensitive ion channels such as TRPV1 –

which is expressed in these nerve fibers – bylocally released inflammatory mediators is

responsible for the increased heat sensitivity

after freeze lesion (Patapoutian et al. 2003). Thesensitization to heat stimuli of spinal nociceptive

neurons after freeze injury has also been demon-

strated in rat and thus contributes to the develop-ment of heat hyperalgesia (Khasabov et al. 2001).

Patterns of ▶Mechanical HyperalgesiaAfter freezing the skin a characteristic pattern of

mechanical hyperalgesia develops to punctuate

stimulation (pin-prick hyperalgesia), to pressurestimulation, and to impact stimulation of the

treated skin area. Increased sensitivity to non-

noxious mechanical stimulation (brush-evoked;Allodynia) is not observed. The alterations

of sensitivity to different types ofmechanical stim-

uli at the site of the freeze injury (primary zone or1#) and the area surrounding the site of injury

(secondary zone or 2#) are described as follows:

Brush-Evoked HyperalgesiaBrush-evoked hyperalgesia or allodynia (for-

merly also called hyperesthesia), normally occur-ring in the 1# and 2# zone, is not consistently

found in the 2# zone and only rarely found in the

1# zone of the freeze model (Kilo et al. 1994).Mechanical allodynia is mediated by an enhanced

central processing of normal sensory input com-

ing from myelinated, mechano-sensitive A fibers(Ab fibers) that transmit non-painful, tactile sen-

sations (Torebjork et al. 1992; Treede et al. 2004).

Allodynia after capsaicin application is found inthe primary and secondary hyperalgesic zone and

results from central plasticity induced and

sustained by persistent nociceptor activity fromthe primary zone. After freezing no psychophys-

iological correlate of Ab fiber activation is

reported, suggesting that a lack of activity of Abfibers together with the limited ongoing activity

of nociceptors may explain the lack of allodynia.

Pin-Prick HyperalgesiaPin-prick hyperalgesia tested by punctuate stimu-

lation of the skin develops in the primary and

secondary zone after freezing the skin in a mannervery similar to the pattern of pin-prick hyperalgesia

observed after capsaicin application (Kiloet al. 1994). In the 1# zone a sensitization of

C-nociceptors to mechanical stimulation leads to

an increased input to the spinal cord. Astonishinglyonly a few studies have shown a peripheral sensi-

tization of C or Ad fibers to suprathreshold

mechanical stimuli, and mechanical activationthresholds remained unchanged (Cooper et al.

1991; Schmelz et al. 1996). However, the normally

mechano-insensitive class of nociceptors is sensi-tized by repeatedmechanical stimulation and could

contribute to the primary mechanical hyperalgesia

(Schmidt et al. 2000). Which fiber types contributeto the central sensitization resulting in the pin-prick

hyperalgesia in the freeze model is not clear, but

after triggering the central sensitization, no ongo-ing activity of these nociceptors is required. The

hyperalgesia in the 2# zone surrounding the injured

skin site is also caused by central sensitizationfollowing excitation of C or Ad nociceptors in

the injured area that facilitate Ad fiber input from

the unlesioned secondary zone.

Hyperalgesia to Impact StimuliC and Ad fiber nociceptors are able to encodeimpacts of different strengths and after sensitization

these fibers mediate hyperalgesia to impact stimuli

(Koltzenburg and Handwerker 1994). The freezinglesion, in contrast to capsaicin application, induced

this special type of hyperalgesia in the primary zone

(Kilo et al. 1994). Maybe due to a long lasting andsevere inflammatory tissue damage, that again

induces the sensitization of mechano- and/or

polymodal nociceptors.

References

Abbadie, C., Honore, P., & Besson, J. M. (1994). Intensecold noxious stimulation of the rat hindpaw inducesc-fos expression in lumbar spinal cord neurons.Neuroscience, 59, 457–468.

Ali, Z., Meyer, R. A., & Campbell, J. N. (1996). Secondaryhyperalgesia tomechanical but not heat stimuli followinga capsaicin injection in hairy skin. Pain, 68, 401–411.

Belmonte, C., Brock, J. A., & Viana, F. (2009). Convertingcold into pain.Experimental BrainResearch, 196, 13–30.

F 1312 Freezing Model of Cutaneous Hyperalgesia

Campero, M., Serra, J., & Ochoa, J. L. (1996).C-polymodal nociceptors activated by noxious lowtemperature in human skin. The Journal of Physiology,497(Pt 2), 565–572.

Cooper, B., Ahlquist, M., Friedman, R. M., Loughner, B.,& Heft, M. (1991). Properties of high-threshold mech-anoreceptors in the oral mucosa I. Responses todynamic and static pressure. Journal of Neurophysiol-ogy, 66, 1272–1279.

Doyle, C. A., & Hunt, S. P. (1999). A role for spinallamina I neurokinin-1-positive neurons in coldthermoreception in the rat. Neuroscience, 91, 723–732.

Foulkes, T., & Wood, J. N. (2007). Mechanisms of coldpain. Channels (Austin, Tex.), 1, 154–160.

Khasabov, S. G., Cain, D. M., Thong, D., Mantyh, P. W.,& Simone, D. A. (2001). Enhanced responses of spinaldorsal horn neurons to heat and cold stimuli followingmild freeze injury to the skin. Journal of Neurophysi-ology, 86, 986–996.

Kilo, S., Schmelz, M., Koltzenburg, M., & Handwerker,H. O. (1994). Different patterns of hyperalgesiainduced by experimental inflammation in humanskin. Brain, 117, 385–396.

Koltzenburg, M., & Handwerker, H. O. (1994). Differen-tial ability of human cutaneous nociceptors to signalmechanical pain and to produce vasodilatation. TheJournal of Neuroscience, 14, 1756–1765.

Lewis, T., & Love, W. S. (1926). Vascular reactions of theskin to injury. Part III.– Some effects of freezing, ofcooling and of warming. Heart, 13, 27–60.

Patapoutian,A., Peier, A.M., Story,G.M.,&Viswanath,V.(2003). ThermoTRP channels and beyond:Mechanismsof temperature sensation. Nature Reviews Neurosci-ence, 4, 529–539.

Schmelz, M., Schmidt, R., Ringkamp, M., Forster, C.,Handwerker, H. O., & Torebjork, H. E. (1996). Limi-tation of sensitization to injured parts of receptivefields in human skin C-nociceptors. ExperimentalBrain Research, 109, 141–147.

Schmidt, R., Schmelz, M., Torebjork, H. E., &Handwerker, H. O. (2000). Mechano-insensitivenociceptors encode pain evoked by tonic pressure tohuman skin. Neuroscience, 98, 793–800.

Simone, D. A., & Kajander, K. C. (1996). Excitation of ratcutaneous nociceptors by noxious cold. NeuroscienceLetters, 213, 53–56.

Simone, D. A., & Kajander, K. C. (1997). Responses ofcutaneous a-fiber nociceptors to noxious cold. Journalof Neurophysiology, 77, 2049–2060.

Torebjork, H. E., Lundberg, L. E., &LaMotte, R.H. (1992).Central changes in processing of mechanoreceptiveinput in capsaicin-induced secondary hyperalgesia inhumans. The Journal of Physiology, 448, 765–780.

Treede, R. D., Handwerker, H. O., Baumg€artner, U.,Meyer, R. A., & Magerl, W. (2004). Hyperalgesiaand allodynia: Taxonomy, assessment, and mecha-nisms. In K. Brune & H. Handwerker (Eds.),Hyperalgesia: Molecular mechanisms and clinicalimplications. Seattle: IASP Press.

Zimmermann, K., Leffler, A., Babes, A., Cendan, C. M.,Carr, R. W., Kobayashi, J., Nau, C., Wood, J. N., &Reeh, P. W. (2007). Sensory neuron sodium channelNav1.8 is essential for pain at low temperatures.Nature, 447, 855–858.

Frequency of Low Back Pain

▶Low Back Pain, Epidemiology

Frequency of Ultrasound Treatment

Definition

The most commonly used frequencies are in the

range of 0.8–1.1 MHz, although frequencies

around 3.0 MHz are also fairly common.

Cross-References

▶Ultrasound Therapy of Pain from the

Musculoskeletal System

Frequency-dependent NociceptiveFacilitation

▶Windup of Spinal Cord Neurons

Freund’s Complete Adjuvant

Synonyms

FCA

Definition

Freund’s complete adjuvant (FCA) isa suspension of heat-killed mycobacterium in

neutral oil, usually paraffin or mineral oil. Sus-

pension is often achieved by ultrasonication.

Freund’s Complete Adjuvant 1313 F

F

Cross-References

▶Arthritis Model, Adjuvant-induced Arthritis

Friction

▶Massage and Pain Relief Prospects

Friction Massage

▶Massage, Basic Considerations

Frontal-Posterior NeckElectromyographic SensorPlacement

Definition

Frontal-posterior neck electromyographic sen-sor placement is an approach designed to assess

muscle activity across a broad region, ranging

from the back of the neck to the front of thehead.

Cross-References

▶ Psychophysiological Assessment of Pain

Frustration

▶Anger and Pain

Fulcrum

Definition

The fulcrum is a pivot about which a lever turns.

Cross-References

▶ Sacroiliac Joint Pain

Functional

Definition

Functional is a term used before a symptom or

disease to describe a process where a symptom or

disease cannot be explained by any lesion,change in structure, or derangement of an organ.

Cross-References

▶ Functional Abdominal Pain in Children

Functional Abdominal Pain

▶Descending Modulation of Visceral Pain▶Visceral Pain Model, Irritable Bowel

Syndrome Model

Functional Abdominal Pain inChildren

Sara E. WilliamsDivision of Pediatric Gastroenterology, Medical

College of Wisconsin, Milwaukee, WI, USA

Synonyms

Chronic abdominal pain; Recurrent abdominal

pain (RAP)

Definition

The term “functional abdominal pain” (FAP)

refers to chronic or recurrent abdominal pain

F 1314 Friction

without evidence of a pathologic or organic con-dition. FAP is included as a diagnostic category

among the childhood functional gastrointestinaldisorders (FGID) as defined by the Rome criteria

(Rasquin et al. 2006). FAP is considered

a diagnosis of exclusion, with criteria only requir-ing the presence of episodic or continuous

abdominal pain that is not better defined by

another FGID or related to an organic process(e.g., anatomic, metabolic, infectious, or inflam-

matory disorder). FAP Syndrome is also

described in the Rome Criteria, which requiresthe additional presence of disability related to

pain (e.g., school absences) and other somatic

symptoms (e.g., headache). Within the Romecriteria, there are other pain-related FGIDs that

are not defined as FAP because the presence of

associated symptoms qualifies as a separate diag-nosis. For example, Irritable Bowel Syndrome

(IBS) is defined as abdominal pain associated

with changes in and relief by bowel movements.As a result, clinically, FAP typically describes

a small number of FGID patients with abdominal

pain. However, in the research setting, it is morecommon for FAP to be used as a term to describe

abdominal pain conditions that are not associated

with organic disease in general.

Introduction

Abdominal pain is a common complaint of

childhood. Originally identified in the pediatricliterature in the 1950s, “recurrent abdominal

pain” was defined as abdominal pain severe

enough to interfere with normal activities(Apley and Naish 1958). It was described as

a common occurrence among school-aged chil-

dren, with a greater prevalence in females thanmales (Apley 1975). More recent population

studies have found that it is common for chil-

dren to experience abdominal pain at somepoint during development, with up to 43 % of

school children reporting transient abdominal

pain (Roth-Isigkeit et al. 2005) and 10–15 % ofchildren reporting chronic abdominal pain

problems (Liakopoulou-Kairis et al. 2002).

Studies of FAP prevalence among pediatric

patients in the medical setting have shown that2–4 % of all pediatric primary care patients are

seen for abdominal pain complaints and up to50 % of pediatric gastroenterology patients

have a pain-related FGID (Nurko and Di

Lorenzo 2008).From a biological standpoint, FAP is under-

stood to be a physiological disorder generated

by a combination of disruptions in intestinaland central nervous system activity (Chiou

and Nurko 2010). Changes in intestinal

motility can result in painful muscular spasmsand contractions. Visceral hypersensitivity,

a result of nerves in the gastrointestinal (GI)

tract becoming over sensitized, contributes tothe production of pain or discomfort from nor-

mal stimuli. Finally, communication between

the brain and gut becomes dysregulated,resulting in increased pain signaling and

perception.

From a psychosocial standpoint, disturbancesin mood and functioning amplify illness experi-

ence and adversely affect health status for

patients with FAP. FAP is disruptive to normalchildhood development. FAP is associated with

anxiety, depression, and somatic symptoms; in

addition, FAP is associated with high levels offunctional disability, school absence, and health

care utilization (Campo et al. 2004).

Because of the complex relationship betweenthese factors that contribute to the presentation of

FAP, it is widely agreed that FAP is best under-

stood through a biopsychosocial model (Chiouand Nurko 2010). The biopsychosocial model

“integrates biological science with the unique

features of the individual and determines thedegree to which biological and psychosocial

factors interact to explain the disease, illness,

and outcome” (Drossman 1998, p. 262). In addi-tion to the biological process, psychological,

social, environmental, and behavioral factors

also are recognized as potential contributing andinteracting factors in patients’ experience of

FAP. It is equally important to assess and treat

FAP from a broad perspective. Research hasidentified several factors that may predispose

a child to develop FAP. Genetics play a role in

making it more likely for a child to develop

Functional Abdominal Pain in Children 1315 F

F

physiological disruptions in the GI tract (Talley2008). Early life events, such as premature birth

or early medical procedures, have been identifiedas potential precursors to the development of

visceral hypersensitivity (Miranda 2008). Parent

and family factors also play an important role;there is a clustering of chronic pain in families

that may occur through parental modeling of

illness behavior and/or through shared genetics(Levy et al. 2000).

Characteristics

Many studies have been conducted to examineconcurrent and long-term medical and psychoso-

cial outcomes in children with FAP. Pediatric

FAP patients demonstrate more anxious, depres-sive, and somatic symptoms, experience more

stressful life events, and have more school

absences than well children (e.g., Campo et al.2004; Walker et al. 1993; Walker and Greene

1989). Furthermore, children with FAP have

increased depression, more somatic symptoms,and greater functional impairment compared to

children with organic gastrointestinal disease

(Walker et al. 1991). A long-term follow-upstudy demonstrated that patients with FAP

continued to have more abdominal pain episodes,

greater disability, more functional impairment,and greater health service utilization 5 years

after initial evaluation compared to a well sample

(Walker et al. 1995). In the same study, exami-nation of patients’ subsequent medical diagnoses

revealed that only 1 child out of 31 was later

diagnosed with an organic condition that mayhave accounted for his or her symptoms.

A recent study of adults who had FAP as children

found that one third continued to have abdominalpain into adulthood, in addition to the develop-

ment of other chronic pain conditions (Walker

et al. 2010).Studies of parents of children with FAP have

revealed a high level of anxiety (Garber et al.

1990) as well as a strong history of FGIDs (Levyet al. 2000) compared to parents of well chil-

dren. Parents of children with FAP typically

report high levels of distress about theirchildren’s symptoms, such as describing them-

selves as helpless in dealing with their children’spain and identifying threat of serious disease as

their most central concern (Van Tilburg et al.

2006). These factors may lead parents to reas-sure their children and protect them from harm

by encouraging children to withdraw from activ-

ities. Although parents have good intentions,this type of protective parenting behavior has

been associated with high levels of school

absence and pain-related disability in pediatricFAP patients (e.g., Walker and Zeman 1992). In

contrast, distracting or coping-promoting par-

enting behavior that draws children’s attentionaway from symptoms and encourages participa-

tion in regular activities is associated with fewer

symptom complaints and better psychosocialoutcomes among children with FAP (e.g.,

Walker et al. 2006).

Treatment

Several interventions have been found to be

effective for treating FAP. As stated, it is essen-

tial that FAP is assessed and treated froma biopsychosocial model to ensure that all factors

that contribute to the FAP presentation are

addressed.Medical therapies typically include dietary

changes to improve motility (e.g., increased

fiber intake), medication from the tricyclic anti-depressant or selective serotonin reuptake inhib-

itor classes to regulate visceral hypersensitivity

and the brain-gut pathway (e.g., amitriptyline,citalopram), and other common GI therapies to

regulate the digestive system as a whole (e.g.,

antacid or proton pump inhibitor therapies, sup-plements such as peppermint oil). Regulating the

GI system from the biological standpoint can help

decrease pain and discomfort and is one of theessential features of treating FAP (Nurko and

Di Lorenzo 2008).

Psychological therapies have been found tohave a promising evidence base for pediatric

FAP. Treatment typically involves cognitive

F 1316 Functional Abdominal Pain in Children

behavioral therapy (CBT) performed individu-ally with the child, or with the child and fam-

ily. The goal of CBT is for children to learnpain coping skills (e.g., relaxation techniques,

positive thinking strategies) and adopt

a functional pain coping approach (e.g.,adopting active and distracting pain coping

skills to continue with regular activities).

Even if a child is seen for individual therapy,it is essential for the treating provider to work

with the child’s school and family to ensure

that the functional pain coping approach issupported in the larger system. Another modal-

ity of psychological therapy is biofeedback,

consisting of focused relaxation practice thathelps children restore physiological balance to

their bodies, which has also been associated

with improvements in pain and functioningamong children with FAP (Schurman et al.

2010). A recent review of psychological ther-

apies for youth with chronic pain found thatcognitive behavioral therapy and relaxation

techniques are effective in reducing pain

severity and frequency, as well as havea lasting effect for symptom improvement

(Eccleston et al. 2009).

Summary

FAP is a common complaint of childhood that

has been extensively studied in the literature.

FAP is a physiological disruption of the GItract in the absence of organic disease. Pedi-

atric FAP patients experience high levels of

disability and psychological distress. Further-more, many patients who experience FAP as

children report higher levels of pain, func-

tional disability, and health service utilizationas adults, and a significant proportion go on to

develop other chronic pain problems. From

a biopsychosocial perspective, the role of cen-tral sensitization of pain perception in the

brain, in addition to ongoing psychological

and social stressors, likely combine to influ-ence maintenance or persistence of pain.

These negative concurrent and long-term

emotional and behavioral outcomes under-score the significant potential impact of FAP

on children’s lives and futures, adding to theimportance of improving the understanding

and treatment of patients with these conditions

through a biopsychosocial approach.

References

Apley, J. (1975). The child with abdominal pains. London:Blackwell.

Apley, J., & Naish, N. (1958). Recurrent abdominal pain:A field survey of 1,000 school children. Archives ofDisease in Childhood, 33, 165–170.

Campo, J., Bridge, J., Ehmann, M., Altman, S., Lucas, A.,Birmaher, B., et al. (2004). Recurrent abdominal pain,anxiety, and depression in primary care. Pediatrics,113, 817–824.

Chiou, E., & Nurko, S. (2010). Management of functionalabdominal pain and irritable bowel syndrome in chil-dren and adolescents. Expert Review of Gastroenter-ology & Hepatology, 4, 293–304.

Drossman, D. A. (1998). Gastrointestinal illness and thebiopsychosocial model. Psychosomatic Medicine, 60,258–267.

Eccleston, C., Palermo, T. M., Williams, A. C. D. C.,Lewandowski, A., &Morley, S. (2009). Psychologicaltherapies for the management of chronic and recurrentpain in children and adolescents. Cochrane Databaseof Systematic Reviews, (2):1–50.

Garber, J., Zeman, J., & Walker, L. S. (1990). Recurrentabdominal pain in children: Psychiatric diagnoses andparental psychopathology. Journal of the AmericanAcademy of Child and Adolescent Psychiatry, 29,648–656.

Levy, R. L., Whitehead, W. E., Von Korff, M. R., & Feld,A. D. (2000). Intergenerational transmission of gastro-intestinal illness behavior. The American Journal ofGastroenterology, 95, 451–456.

Liakopoulou-Kairis, M., Alifieraki, T., Protagora, D.,Korpa, T., Kondyli, K., Dimosthenous, E., et al.(2002). Recurrent abdominal pain and headache.European Child & Adolescent Psychiatry, 11,115–122.

Miranda, A. (2008). Early life events and the developmentof visceral hyperalgesia. Journal of Pediatric Gastro-enterology and Nutrition, 47, 680–684.

Nurko, S., & Di Lorenzo, C. (2008). Functional abdominalpain: Time to get together and move forward. Journalof Pediatric Gastroenterology and Nutrition, 47,679–680.

Rasquin, A., Di Lorenzo, C., Forbes, D., Guiraldes, E.,Hyams, J. S., Staiano, A., et al. (2006). Childhoodfunctional gastrointestinal disorders. Gastroenterol-ogy, 130, 1527–1537.

Functional Abdominal Pain in Children 1317 F

F

Roth-Isigkeit, A., Thyen, U., Stoven, H.,Schwarzenberger, J., & Schmucker, P. (2005). Painamong children and adolescents: Restrictions in dailyliving and triggering factors. Pediatrics, 115, e152–e162.

Schurman, J. V., Wu, Y. P., Grayson, P., & Friesen, C. A.(2010). A pilot study to assess the efficacy of biofeed-back-assisted relaxation training as an adjunct treat-ment for pediatric functional dyspepsia associatedwith duodenal eosinophilia. Journal of Pediatric Psy-chology, 35, 837–847.

Talley, N. J. (2008). Genetics and functional bowel dis-ease. Journal of Pediatric Gastroenterology andNutrition, 47, 680–682.

Van Tilburg, M. A. L., Venepalli, N., Ulshen, M.,Freeman, K. L., Levy, R., & Whitehead, W. E.(2006). Parents’ worries about recurrent abdominalpain in children. Gastroenterology Nursing, 29,50–55.

Walker, L. S., & Greene, J. W. (1989). Children withrecurrent abdominal pain and their parents: Moresomatic complaints, anxiety, and depression thanother patient families? Journal of Pediatric Psychol-ogy, 14, 231–243.

Walker, L. S., & Zeman, J. L. (1992). Parental response tochild illness behavior. Journal of Pediatric Psychol-ogy, 17, 49–71.

Walker, L. S., Garber, J., & Greene, J. W. (1991). Soma-tization symptoms in pediatric abdominal painpatients: Relation to chronicity of abdominal painand parent somatization. Journal of Abnormal ChildPsychology, 19, 379–394.

Walker, L. S., Garber, J., & Greene, J. (1993). Psycho-logical correlates of recurrent abdominal pain:A comparison of pediatric patients with recurrentabdominal pain, organic illness, and psychiatric dis-orders. Journal of Abnormal Psychology, 102,248–258.

Walker, L. S., Garber, J., Van Slyke, D. A., & Greene,J. W. (1995). Long-term health outcomes in patientswith recurrent abdominal pain. Journal of PediatricPsychology, 20, 233–245.

Walker, L. S., Williams, S. E., Smith, C. A., Garber, J.,Van Slyke, D. A., & Lipani, T. A. (2006). Parentattention versus distraction: Impact on symptomcomplaints by children and adolescents with andwithout chronic functional abdominal pain. Pain,122, 43–52.

Walker, L. S., Dengler-Crish, C. M., Rippel, S., &Bruehl, S. (2010). Functional abdominal pain in child-hood and adolescence increases risk for chronic pain inadulthood. Pain, 150, 568–572.

Functional Abilities Evaluation

▶Disability, Functional Capacity Evaluations

Functional Aspects of Visceral Pain

▶ Psychiatric Aspects of Visceral Pain

Functional Bowel Disorder

Definition

Functional bowel disorder is a disorder or disease

where the primary abnormality is an altered phys-iological function (the way the body works)

rather than an identifiable structural or biochem-

ical cause. A functional disorder does not showany evidence of an organic or physical disease. It

is a disorder that generally cannot be diagnosed in

a traditional way, as an inflammatory, infectious,or structural abnormality that can be seen

by commonly used examination, x-ray, or labo-

ratory test.

Cross-References

▶Descending Modulation of Visceral Pain

▶Visceral Pain Model, Irritable BowelSyndrome Model

Functional Brain Imaging

Definition

Functional brain imaging is a noninvasive neuro-

imaging technique that detects changes in brain

metabolism or neuronal activity in response to sen-sory, motor or cognitive tasks, giving information

regarding the function of specific brain regions; see

also ▶ functional imaging and ▶ fMRI.

Cross-References

▶Thalamus and Visceral Pain Processing

(Human Imaging)

F 1318 Functional Abilities Evaluation

Functional Capacity

Definition

For United States Social Security purposes, func-

tional capacity represents the measure ofa person’s ability to perform particular work-

related physical and mental activities.

Cross-References

▶Disability Evaluation in the Social Security

Administration

Functional Capacity Assessment

▶Disability, Functional Capacity Evaluations

Functional Capacity Battery

▶Disability, Functional Capacity Evaluations

Functional Capacity Evaluation

Synonyms

FCE

Definition

Functional capacity evaluation systematically

measures the worker’s ability to carry out work

tasks safely. It includes trait-oriented systems ofnorm-referenced assessment, e.g., the Baltimore

Therapeutic Equipment (BTE) (http://www.

bteco.com/). The results demonstrate the indi-vidual’s physical functional capacity, e.g.,

lifting capacity, fine motor dexterity, work tol-

erance, and preparedness for returning to work.

FCE has been criticized for the lack of corre-spondence between the individual’s functional

capacity and a job’s real requirements: It doesnot demonstrate the individual’s opportunities

of returning to, and retaining, a job. Synonyms:

physical capacity evaluation; work capacityevaluation.

Cross-References

▶Disability, Functional Capacity Evaluations▶Vocational Counseling

Functional Changes in SensoryNeurons Following Spinal CordInjury

▶ Functional Changes in Sensory Neurons

Following Spinal Cord Injury in Central Pain

Functional Changes in SensoryNeurons Following Spinal CordInjury in Central Pain

Jing-Xia Hao1 and Xiao-Jun Xu2

1Department of Physiology and Pharmacology,

Karolinska Institutet, Stockholm, Sweden2Department of Physiology and Pharmacology,

Section of Integrative Pain Rsearch Karolinska

Institutet, Stockholm, Sweden

Synonyms

Central pain; Functional changes in sensory

neurons following spinal cord injury

Definition

Chronic pain is a common consequence of spi-

nal cord injury (SCI), often mixed with

Functional Changes in Sensory Neurons Following Spinal Cord Injury in Central Pain 1319 F

F

nociceptive, visceral, and neuropathic compo-nents. Neuropathic SCI pain is a form of central

pain that represents a major challenge for thoseresponsible for clinical pain management

(Siddall et al. 2002). Several models of SCI

have been developed in recent years that allowthe direct examination of neuronal mechanisms

mediating SCI-induced central pain (Vierck

et al. 2000).▶Central pain refers to neuropathic pain asso-

ciated with a lesion of the central nervous system.

▶ Spinal cord injury pain (SCI pain) isa particular form of central pain seen in patients

with spinal cord injury or diseases of the spinal

cord, e.g., syringomyelia and tumors. The dorsalhorn of the spinal cord is the first relay point for

somatosensory perception. Neurons in the dorsal

horn process sensory input and transmit thisinformation to higher brain centers, while initiat-

ing motor and autonomic reflexes. Sensory neu-

rons in the dorsal horn can be classified into threetypes with respect to responses to mechanical

stimulation: ▶ low-threshold (LT) neurons that

respond maximally to innocuous stimuli,▶wide dynamic range (WDR) neurons that give

graded responses to innocuous and noxious stim-

ulation, and ▶ high-threshold (HT) neurons thatrespond exclusively to noxious stimulation.

Introduction

Chronic pain is a common consequence of spinalcord injury (SCI), often mixed with nociceptive,

visceral, and neuropathic components. Neuro-

pathic SCI pain is a form of central pain thatrepresents a major challenge for those responsi-

ble for clinical pain management (Siddall et al.

2002). Several models of SCI have beendeveloped in recent years that allow the direct

examination of neuronal mechanisms mediating

SCI-induced central pain (Vierck et al. 2000).

Characteristics

In recent years, several studies have been

published characterizing the response patterns

of dorsal horn neurons in rats with spinal cordinjury and behaviors suggesting the presence of

SCI pain. The models of injury employed includephotochemically induced ischemic SCI (Hao

et al. 1992; Hao et al. 2004), excitoxicity associ-

ated with intraspinal injection of quisqualic acid(Yezierski and Park 1993), contusion (Drew et al.

2001; Hoheisel et al. 2003; Hains et al. 2003a),

transection (Scheifer et al. 2002; Zhang et al.2005), and hemisection (Hains et al. 2003b; Lu

et al. 2008). Below are described four functional

characteristics of dorsal horn neurons that havebeen described as changing following spinal cord

injury.

Receptive FieldsThe proportion of dorsal horn neurons without

a demonstrable mechanical receptive field (RF)is increased after spinal cord injury (Hoheisel

et al. 2003; Hao et al. 2004). These neurons tend

to have high-frequency ongoing activity and areclustered around the rostral end of the injured

spinal segment. This suggests that the normal

afferent input (either direct or indirect) to someof these neurons has been interrupted by injury,

resulting in a lack of RF. The original RFs of

these neurons are likely to be on skin areas ren-dered anesthetic by the injury. Abnormal sponta-

neous discharges of these neurons, especially

those projecting to higher centers, may give riseto dysesthesia or pain referred to the anesthetic

skin areas caudal to the lesion. This type of pain is

referred to as below level pain and is a majorcomponent of the pain syndrome in patients

with SCI (Siddall et al. 2002). There are also

behavioral indications of below level pain in ratmodels in the form of autotomy and excessive

scratching/grooming leading to skin damage

(Vierck et al. 2000).

Spontaneous ActivityIn our analysis of activity of dorsal horn neuronsafter SCI, we have described animals with seg-

mental allodynia, and these rats have a larger

proportion of neurons with high rates of sponta-neous activity (SA) (Hao et al. 2004). These

neurons were located near the edge of the

lesion site. This is similar to the results of

F 1320 Functional Changes in Sensory Neurons Following Spinal Cord Injury in Central Pain

Hoheisel et al. (2003) and Zhang et al. (2005)who found that neurons close to a spinal contu-

sion or transection exhibited increased levels ofongoing activity. Yezierski and Park (1993) and

Drew et al. (2001) have also reported a higher

level of such activity in neurons in spinallyinjured rats. In our sample, the level of spontane-

ous activity of HT neurons and neurons without

receptive fields was significantly higher than thatof LT or WDR neurons. Interspike interval anal-

ysis indicated that the discharges were irregular

and burst-like in the majority of SA neurons.Since HT neurons receive input from nociceptors

and are involved in pain signaling (Chung et al.

1986), the high rate of SA in HT neurons maygive rise to spontaneous pain sensations in skin

areas with sensory loss. Hoheisel et al. (2003)

have also noted several forms of pathophysiolog-ical background activity that were not seen in

normal animals, including bursting-like activity.

Changes in the Functional Type of NeuronsRecordedIn normal rats, the proportion of different neuro-nal types recorded depends on several factors,

including classification criteria used, type of

preparations, anesthesia, etc. In our study, weused an intact rat preparation with urethane anes-

thesia and we recorded from neurons with

response characteristics resembling those of LT,WDR, and HT neurons (Chung et al. 1986). The

relative proportion of these neuronal types in

a sample of normal rats was similar to thatreported in most previous studies in the field. By

contrast, considerably more WDR neurons were

encountered in spinally injured rats two to threesegments above the injury (Hao et al. 2004).

Since neurons in normal and injured rats were

recorded from different animals, it is impossibleto know the original phenotype of these WDR

neurons. We have speculated that the increased

proportion of WDR neurons reflects eitherthe appearance of novel innocuous input to HT

neurons or increased responses of LT neurons to

noxious input. Both possibilities imply that thereis an increased excitability in sensory pathways in

the spinal cord underlying behavioral allodynia.

A decrease in inhibitory influences may also

contribute to these functional changes. Drewet al. (2001) have also compared the response

properties of neurons in normal, spinally injurednon-allodynic and allodynic rats. Interestingly,

they observed that the proportion of LT neurons

was increased and they became more commonthan WDR neurons rostrally, but not caudally, to

the lesion site. The difference between our results

and those of Drew et al. (2001) may be due todifferences in classification criteria, since they

did not have HT neurons in their sample.

Responses to Peripheral StimulationMechanical▶ allodynia is a common symptom in

patients with SCI pain (Siddall et al. 2002), andsimilar behavior is consistently observed in rat

models of SCI pain (Xu et al. 1992; Vierck et al.

2000). In support of the behavioral observations,electrophysiological recording of dorsal horn

activity in these animals has revealed increased

neuronal responsiveness to mechanical stimula-tion. This included increased responses of WDR

neurons to brush, pinch, and graded von Frey hair

stimulation, decreased von Frey threshold,increased response of HT neurons, and increases

in afterdischarges (Hao et al. 1992; Yezierski and

Park 1993; Drew et al. 2001; Hains et al. 2003;Hoheisel et al. 2003; Zhang et al. 2005). These

changes are likely to underlie the mechanical

allodynia observed following spinal injury. Simi-larly, we have also found that the responses of

dorsal horn neurons to cold stimulation increased

after SCI, corresponding to cold allodynia in theserats. A higher percentage of WDR and LT neu-

rons, which normally react poorly to cold, react to

cold stimulation in allodynic rats (Hao et al. 2004).

Conclusions

Abnormal electrophysiological properties of dor-

sal horn neurons can be documented in rats withchronic pain-related behaviors after SCI. Based on

the similarities between the neuronal and behav-

ioral responses, it is likely that neuronal changes inthe dorsal horn around the level of injury are

responsible for the behavioral manifestation of

pain-like responses. Some of the abnormalities

Functional Changes in Sensory Neurons Following Spinal Cord Injury in Central Pain 1321 F

F

are most probably the result of deafferentation inthe zone immediately rostral to the spinal lesion.

The reduction of spinal GABAergic inhibition hasalso been shown to be involved in the mechanical

hypersensitivity of dorsal horn neurons after SCI

(Hao et al. 1992; Lu et al. 2008). Moreover, SCIinduces complex neurochemical changes in areas

rostral to the lesion, which may also contribute to

the neuronal abnormalities. It is important to notethat some of neuronal changes observed in spi-

nally injured rats, noticeably spontaneous hyper-

activity in the dorsal horn, have also been seen inpatients with SCI pain and lesions of the dorsal

root entry zone; targeting areas of spontaneous

activity have been shown to alleviate pain (Falciet al. 2002).

References

Chung, J. M., Surmeier, D. J., Lee, K. H., et al. (1986).Classification of primate spinothalamic and somato-sensory thalamic neurons based on cluster analysis.Journal of Neurophysiology, 56, 308–327.

Drew, G. M., Siddal, P. J., & Duggan, A. W. (2001).Responses of spinal neurons to cutaneous and dorsalroot stimuli in rats with mechanical allodynia aftercontusive spinal cord injury. Brain Research, 893,59–69.

Falci, S., Best, L., Bayles, R., et al. (2002). Dorsal rootentry zone microcoagulation for spinal cord injury-related central pain: Operative intramedullary electro-physiological guidance and clinical outcome. Journalof Neurosurgery, 97, 193–200.

Hains, B. C., Klein, J. P., Saab, C. Y., et al. (2003a).Upregulation of sodium channel Nav1.3 and func-tional involvement in neuronal hyperexcitabilityassociated with central neuropathic pain afterspinal cord injury. Journal of Neuroscience, 23,8881–8892.

Hains, B. C., Willis, W. D., & Hulsebosch, C. E. (2003b).Serotonin receptors5-HT1A and 5-HT3 reduceshyperexcitability of dorsal horn neurons after spinalcord hemisection injury in rat. Experimental BrainResearch, 149, 174–186.

Hao, J. X., Xu, X. J., Yu, Y. X., et al. (1992). Baclofenreverses the hypersensitivity of dorsal horn widedynamic range neurons to low threshold mechanicalstimuli after transient spinal cord ischemia: Implica-tion for a tonic GABAergic inhibitory control uponmyelinated fiber input. Journal of Neurophysiology,68, 392–396.

Hao, J. X., Kupers, R., & Xu, X. J. (2004). Responsecharacteristics of spinal cord dorsal horn neurons in

chronic allodynic rats after spinal cord injury. Journalof Neurophysiology, 92, 1391–1399.

Hoheisel, U., Scheifer, C., Trudrung, P., et al. (2003).Pathophysiological activity in rat dorsal horn neuronsin segments rostral to a chronic spinal cord injury.Brain Research, 974, 134–145.

Lu, Y., Zheng, J. H., Xiong, L. Z., Zimmermann, M., &Yang, J. (2008). Spinal cord injury-induced attenua-tion of GABAergic inhibition in spinal dorsal horncircuits is associated with down-regulation of the chlo-ride transporter KCC2 in rat. The Journal of Physiol-ogy, 586, 5701–5715.

Scheifer, C., Hoheisel, U., Trudrung, P., et al. (2002). Ratswith chronic spinal cord transection as a possiblemodel for the at-level pain of paraplegic patients.Neuroscience Letters, 323, 117–120.

Siddall, P. J., Yezierski, R. P., & Loeser, J. D. (2002).Taxonomy and epidemiology of spinal cord injurypain. In R. P. Yezierski & K. J. Burchiel (Eds.), Spinalcord injury pain: Assessment, mechanisms, manage-ment (pp. 9–24). Seattle: IASP Press.

Vierck, C. J., Jr., Siddall, P., & Yezierski, R. P. (2000).Pain following spinal cord injury: Animal models andmechanistic studies. Pain, 89, 1–5.

Xu, X. J., Hao, J. X., Aldskogius, H., et al. (1992).Chronic pain-related syndrome in rats after ischemicspinal cord lesion: A possible animal model for painin patients with spinal cord injury. Pain, 48,279–290.

Yezierski, R. P., & Park, S. H. (1993). The mechanosen-sitivity of spinal sensory neurons following intraspinalinjections of quisqualic acid in therat. NeuroscienceLetters, 157, 115–119.

Zhang, H. J., Xie, W. R., & Xie, Y. K. (2005). Spinal cordinjury triggers sensitization of wide dynamic rangedorsal horn neurons in segments rostral to the injury.Brain Research, 1055, 103–110.

Functional Changes in Thalamus

▶Thalamic Plasticity and Chronic Pain

Functional GastrointestinalDisorders

Definition

Functional gastrointestinal disorders are

a collection of symptom based gastrointestinal

conditions for which no biomedical abnormalitycan be found to explain symptoms. Similar to

other functional conditions such as fibromyalgia.

F 1322 Functional Changes in Thalamus

Cross-References

▶Thalamus and Visceral Pain Processing

(Human Imaging)

Functional Imaging

Definition

Functional imaging is a general term used to

describe methodologies that allow function to be

located either spatially or temporally within thebrain (and other organs). The methods allow detec-

tion of molecular signals that indicate the presence

of biochemical activity and changes, such as cellactivity or death. They are generally noninvasive

and used for human studies. The term “neuroimag-

ing” is often usedwhen applied specifically to brainstudies. Methods include: Functional Magnetic

Resonance Imaging (FMRI), Positron Emission

Tomography (PET), Magneto-Encephalography(MEG), and Electro-Encephalography (EEG).

Cross-References

▶ Functional Imaging of Cutaneous Pain▶Hippocampus and Entorhinal Complex:

Functional Imaging

▶ Insular Cortex, Neurophysiology, andFunctional Imaging of Nociceptive Processing

▶ Psychiatric Aspects of Visceral Pain

Functional Imaging of CutaneousPain

J€urgen LorenzFaculty of Life Science, Competence Center

Gesundheit, University of Applied ScienceHamburg, Hamburg, Germany

Synonyms

Cutaneous pain; Functional imaging

Definition

This chapter reviews methodologies that monitor

the spatial distribution of cerebral metabolic,hemodynamic, electrical, or magnetic reactions

by which areas of the brain are identified that are

active during the processing and perception ofexperimentally induced or clinical pain originat-

ing in the human skin.

Characteristics

Functional imaging techniques applied for the study

of cutaneous pain are▶positron emission tomogra-

phy (PET), ▶ functional magnetic resonance imag-ing (fMRI), multi-lead electroencephalography

(EEG), and ▶magnetoencephalography (MEG).

PET measures cerebral blood flow, glucosemetabolism, or neurotransmitter kinetics. A very

small amount of a labeled compound (called the

radiotracer) is intravenously injected into thepatient or volunteer. During its uptake and

decay in the brain, the radionuclide emits

a positron, which, after traveling a short distance,“annihilates” with an electron from the surround-

ing environment. This event results in the emis-

sion of two gamma rays of 511 keV in oppositedirections, the coincidence of which is detected

by a ring of photomultipliers inside the scanner.

In case of the most common use of O15-waterinjection, counting and spatial reconstruction of

these occurrences within the brain anatomy allow

visualization of the regional cerebral blood flowresponse (rCBF) as an indicator of neuronal

activity. Usually scans during painful stimulation

are statistically compared with scans during theresting state or non-painful stimulation (blocked

design) and plotted as 3-dimensional color-coded

t- or Z-score maps.FMRI images blood oxygenation using the

so-called BOLD (blood oxygen level-dependent)technique which exploits the phenomenon that

oxygenated and deoxygenated hemoglobin pos-

sess different magnetic properties. Both the rCBFusingO15-water PET and the BOLD technique rely

on neurovascular coupling mechanisms that

are not yet fully understood, but which

Functional Imaging of Cutaneous Pain 1323 F

F

overcompensate local oxygen consumption, thuscausing a flowof oxygenated blood into neuronally

active brain areas in excess of that utilized.EEG and MEG are noninvasive neurophysio-

logical techniques that measure the respective

electrical potentials and magnetic fields gener-ated by neuronal activity of the brain and

propagated to the surface of the skull where

they are picked up with EEG-electrodes or, inthe case of its magnetic counterpart, received by

SQUID (supra conducting quantum interference

device) sensors located outside the skull.Compared with PET and fMRI, EEG and MEG

are direct indicators of neuronal activity and yield

a higher temporal resolution of the investigatedbrain function. The spatial distributions of EEG

potentials and MEG fields at characteristic

time points following noxious stimulation(▶ noxious stimulus) are analyzed using an

inverse mathematical modeling approach called

equivalent current dipole (ECD) reconstruction.An ECD evoked by painful stimuli hence repre-

sents a source model of pain-relevant activity

within the brain. The spatial acuity of MEG ishigher than that of EEG because the latter mea-

sures the extracellular volume currents that are

distorted by the differentially conducting tissuessuch as gray and white matter, cerebrospinal

fluid, durae, and bone. In contrast, MEG mea-

sures the magnetic field perpendicular to theintracellular currents undistorted by the sur-

rounding tissue. Given the different geometry of

electrical potentials and magnetic fields, MEG ispredominantly sensitive to dipoles oriented tan-

gentially to the head convexity, whereas EEG

depends primarily on radial but also on tangentialdipoles. Functional imaging using PET, fMRI,

EEG, and MEG has substantially increased the

knowledge about the cerebral representation ofpain (Casey 1999) and its modulation by psycho-

logical phenomena (Porro 2003).

A bone of contention in the research fielddealing with the cerebral representation of pain

is the involvement of primary and secondary

somatosensory cortex. When using contact heatto activate ▶ nociceptors, multiple areas of the

brain such as the thalamus, primary (SI) and

secondary (SII) somatosensory cortices, posterior

and anterior parts of the insula, and mid-caudalparts of the anterior cingulate cortex (ACC)

respond to this input in a correlated manner withperceived intensity (Coghill et al. 1999). How-

ever, the touch of the probe or attentional effects

inherent in block designs could explain SI and SIIcortex activity being unrelated to pain. Yet,

if infrared laser stimuli that lack a concomitant

tactile component are applied over a range ofrandomly presented intensities in event-related

designs by MEG (Timmermann et al. 2001) or

fMRI (Bornhoevd et al. 2002), SI activity showsa steady increase with laser heat intensity,

whereas the SII and insula respond robustly to

painful but not or only slightly to non-painfulintensities. Using BOLD responses of FMRI,

Moulton et al. (2012) recently compared different

degrees of non-painful and painful contact heatintensities and found best correlation with heat

rather than pain intensity in contralateral SI and

SII cortices. Discrepancy between laser and con-tact heat may be due to the fact that laser stimuli

involve a very narrow range of pre-pain intensi-

ties. These stimulus–response functions fit withthe behavior of distinct wide dynamic range

(WDR) and nociceptive-specific (NS) neurons

of the dorsal horn, thalamus, and SI cortex(Price et al. 2003). These features and the impor-

tance of a relay of afferent activity in lateral

thalamic nuclei substantiate the key role of SIand SII cortices as part of a lateral pain system

subserving the sensory-discriminative function of

pain (Melzack and Casey 1968; Price 2000).Under conditions of specific psychological inter-

ventions such as hypnosis (Rainville et al. 1997),

pain anticipation (Ploghaus et al. 1999), or▶ placebo cognitions (Petrovic et al. 2002), fron-

tal brain regions such as ACC and the anterior

insula appear to subserve more specifically theaffective-motivational and cognitive component

of pain (Melzack and Casey 1968; Price 2000).

They represent the major targets of the medialpain system given a major afferent input to these

brain areas from medial thalamic nuclei. Other

areas such as ▶ basal ganglia, ▶ cerebellum, andvarious structures within the prefrontal cortex

yielded activation by experimental pain in sev-

eral studies; their role in pain processing,

F 1324 Functional Imaging of Cutaneous Pain

however, remained elusive and is mainlydeduced from their importance in other cognitive,

motor, or behavioral functions.Craig (2003) challenged the concept of

a sensory-discriminative function of pain. An

important component of his hypothesis is theassumption that pain is primarily an interoceptive

perception like hunger, thirst, or itch, originating

in specific spinothalamic tract (STT) neurons ofthe superficial dorsal horn (lamina I). As “labeled

lines,” these STT neurons impinge upon specific

thalamic nuclei, such as the posterior part of theventromedial nucleus (VMpo) and the ventral

caudal part of the mediodorsal nucleus (MDvc),

which relay afferent input to dorsal posteriorinsula and caudal ACC, respectively. These two

pathways are regarded as important elements of

a hierarchical system subserving ▶ homeostasis,linking the sense of the physiological condition of

the body (▶ interoception) with subjective

feelings and emotion. Although the interoceptivefunction of pain is well conceivable, negation of

an exteroceptive function of pain is neither

intuitive nor supported by functional imagingdata (see above). Word descriptors such as those

compiled in the McGill Pain Questionnaire,

e.g., cutting, pinching, stinging, squeezing orcrushing, and many more, express how

a stimulus from outside the body causes pain

and are often used by pain patients to describetheir pain, although there is no exteroceptive

stimulus. In contrast, there is clearly less richness

of exteroceptive sensory descriptors for hunger orthirst, even though the latter are much more

everyday sensations or feelings than pain. Lenz

et al. (2004) electrically stimulated thalamictermination areas of STT neurons in conscious

patients undergoing stereotactic procedures for

the treatment of movement disorders and chronicpain. Patients used mainly exteroceptive words,

rarely internal or emotional phenomena, to

describe their subjective responses to the stimuli.Furthermore, two groups of responses were

observed following stimuli applied to distinct

thalamic locations, a binary response signalingpain, but no non-painful sensation, and an analog

response covering graded intensities across

non-painful and painful sensations. This result is

consistent with a sensory-discriminative orexteroceptive pain function through pathways

that convey alarm according to an all-or-nothingstimulus–response relationship and others that

indicate how strong and where the stimulus is.

The ambiguity of pain as exteroceptive orinteroceptive phenomenon likely relates to the

fact that many painful experiences throughout

the entire life span of an individual derive fromthe skin (burns, cuttings, etc.). The human skin

forms the interface between the body and the

outer world. Cutaneous sensitivity is thereforeprimarily reflecting the capability of the organ-

ism to receive signals from outside the body in

the form of touch, temperature, and painsensations. As a consequence, cutaneous sensi-

tivity primarily subserves an exteroceptive

function. However, pathological changes of theskin due to inflammation or injury lead to pain

that informs the individual about the body rather

than a stimulus from the outer world and, there-fore, serves an interoceptive function. Often the

term interoception is attributed to visceral sensa-

tion, or homeostatic feelings such as hunger andthirst. Yet, inflammatory and injury pain of the

skin are indeed good indications that a change in

the bodily state can also involve a shift fromprimarily exteroceptive to interoceptive cutane-

ous pain function. Sound support for the hypoth-

esis that cutaneous pain inherits bothexteroceptive and interoceptive functions is pro-

vided by a PET imaging study conducted by

Lorenz et al. (2002). These authors addressedthe question of whether nociceptive activity

resulting from two equally painful contact heat

stimuli applied to normal skin or the same skinsensitized by a topical solution of capsaicin

would yield different functional imaging results.

They tested whether the effect of skin sensitiza-tion would be similar to that of pain intensity

observed by the same group in an earlier

study when painful heat was compared withnon-painful warmth (Casey et al. 2001). Thus,

whereas the critical aim of the Lorenz et al.

experiment was to match subjective intensitiesof a slowly ramped and continuously applied

contact heat stimulus across normal and sensi-

tized skin conditions to minimize a confound

Functional Imaging of Cutaneous Pain 1325 F

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0

49 !C

45 !C

41 !C

50 !C

40 !C

Mid CC Mid Ins/S2 Premot C

CBL LTh/Lent n M1/S1

10 20 30 40Time (s)

50 60

0 10 20 30 40Time (s)

50 60

LT.LAT

PFC Perigenual CCMB MTh Ant Ins

Z5

1.6

LT.MED

Interoceptiveheat pain

Exteroceptiveheat pain

RT.MED

OFCAC−PC + 11 SUPRT.LAT

Functional Imaging of Cutaneous Pain,Fig. 1 Stimulus paradigms to differentially manipulatebody-related (interoceptive) and stimulus-related (extero-ceptive) pain processes with positron emission tomogra-phy (PET). The top section shows the temporal profile oftwo slowly ramped heat stimuli reaching different pla-teaus equated for subjective pain intensity. One stimulusis applied on the normal skin of the left volar forearmto approximately 47 #C (solid black), which is 2 #C abovethe average heat pain threshold (dotted black) and felt asa clear, but tolerable pain sensation. Another stimulusis applied to approximately 43 #C on the same skin,when it had been sensitized by a topical solution of cap-saicin (solid red). This treatment caused a drop in the heatpain threshold by approximately 4 #C (dotted red), ren-dering the heat stimulus as painful as the 4 #C moreintense stimulus applied on normal skin. The subtraction

of PET scans between the two conditions (capsaicin-treated minus normal skin) is shown at the bottom ofsection A. Surface-rendered images and median sagittalcuts from both sides, a horizontal slice 11 mm above theAC-PC line, and a superior view are displayed. Theimages demonstrate activity of the midbrain, medial thal-amus, anterior insula, perigenual cingulate, and prefrontalcortex representing the change in the physiological statusof the skin (sensitized vs. normal). The bottom sectionshows the temporal profile of two heat stimuli that wereset to a constant temperature of either 50 #C or 40 #C indifferent blocks and repeatedly applied to different spotsof the normal skin, each contact lasting 5 s. Images com-paring these two stimuli illustrate activity in the lateralthalamus, lenticular nucleus, mid-posterior insula/SII,mid-anterior cingulated, cerebellum, and premotor cortex,the latter extending into the MI/SI region

F 1326 Functional Imaging of Cutaneous Pain

with perceived intensity and test the importanceof the physiological status of the tissue

(interoception), the Casey et al. study tested theimportance of different applied and perceived

intensities of repeated rapidly ramped contact

heat stimuli without changing the tissue status(▶ exteroception). Their results illustrated in

Fig. 1 show that interoceptive and exteroceptive

manipulations of burning pain engage clearlydifferent forebrain structures. Key structures

responding to manipulating the exteroceptive

stimulus condition are the lateral thalamus,lenticular nucleus/putamen, mid-posterior

insula/SII, SI/MI, caudal ACC, premotor cortex,

and cerebellum. In contrast, key structuresresponding to manipulating the interoceptive

stimulus condition are the medial thalamus,

ventral caudate/nucleus accumbens, anteriorinsula, dorsolateral prefrontal and orbitofrontal

cortices, and the perigenual ACC. Notably,

although the perceived intensities were equatedbetween the two skin conditions in the Lorenz

et al. study, pain on sensitized skin (heat

allodynia) yielded greater negative affectaccording to ratings subjects made using both

a visual analog scale of “unpleasantness” and

a short form of the McGill Pain Questionnaire atthe end of each scan. This result is consistent with

the close relationship of interoception with

emotion giving rise to intrinsically strongeraffective pain experiences during pathological

tissue states. Furthermore, the involvement of

cerebral motor systems differs between extero-ceptive and interoceptive pain. Whereas

exteroceptive pain recruits brain structures such

as the putamen, motor and premotor cortex, andcerebellum suited to govern an immediate and

spatially guided defense or withdrawal due to

their somatotopic organization (Bingel et al.2004a, b), interoceptive pain engages the ventral

caudate and nucleus accumbens, which are part

of a limbic basal ganglia loop relevant for moti-vational drive of behavior rather than motor

execution. Overall, these results substantiate

suggestions that different projection systemsoriginating in the dorsal horn of the spinal cord

mediate normal pain and pain from sensitized

nociceptors (Hunt and Mantyh 2001). In

differentiating different pain types by their ori-gins from either outside or inside the body, the

brain may engage different behavioral adapta-tions according to the meaning of the pain in

relation to the physiological status of the body.

References

Bingel, U., Gl€ascher, J., Weiller, C., & B€uchel, C. (2004a).Somatotopic representation of nociceptive informa-tion in the putamen: An event related fMRI study.Cerebral Cortex, 14, 1340–1345.

Bingel, U., Lorenz, J., Glauche, V., Knab, R., Gl€ascher,J., Weiller, C., & B€uchel, C. (2004b). Somatotopicorganization of human somatosensory cortices forpain: A single trial fMRI study. NeuroImage, 23,224–232.

Bornhoevd, K., Quante, M., Glauche, V., et al. (2002).Painful stimuli evoke different stimulus–responsefunctions in the amygdala, prefrontal, insula, andsomatosensory cortex: A single trial fMRI study.Brain, 123, 601–619.

Casey, K. L. (1999). Forebrain mechanisms of nociceptionand pain: Analysis through imaging. Proceedings ofthe National Academy of Sciences of the United Statesof America, 96, 7668–7674.

Casey, K. L., Morrow, T. J., Lorenz, J., et al. (2001).Temporal and spatial dynamics of human cerebralactivation pattern during heat pain: Analysis of posi-tron emission tomography. Journal of Neurophysiol-ogy, 85, 951–959.

Coghill, R. C., Sang, C. N., Maisog, J. M., et al. (1999).Pain intensity processing in the human brain:A bilateral, distributed mechanisms. Journal ofNeurophysiology, 82, 1934–1943.

Craig, A. D. (2003). A new view of pain as a homeostaticemotion. Trends in Neurosciences, 6, 303–307.

Hunt, S. P., &Mantyh, P.W. (2001). Themolecular dynam-ics of pain control. Nature Neuroscience, 2, 83–91.

Lenz, F. A., Ohara, S., Gracely, R. H., et al. (2004). Painencoding in the human forebrain: Binary and analogexteroceptive channels. The Journal of Neuroscience,24, 6540–6544.

Lorenz, J., Cross, D. J., Minoshima, S., et al. (2002).A unique representation of heat allodynia in thehuman brain. Neuron, 35, 383–393.

Melzack, R., & Casey, K. L. (1968). Sensory, motiva-tional, and central control determinants of pain. InD. R. Kenshalo (Ed.), The skin senses (pp. 423–443).Springfield Illinois: Thomas.

Moulton, E. A., Pendse, G., Becerra, L. R., & Borsook, D.(2012). BOLD responses in somatosensory corticesbetter reflect heat sensation than pain. The Journal ofNeuroscience, 32(17), 6024–6031.

Petrovic, P., Kalso, E., Petersson, K. M., et al. (2002).Placebo and opioid analgesia – imaging a shared neu-ronal network. Science, 295, 1737–1740.

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Ploghaus, A., Tracey, I., Gati, J. S., Clare, S.,Menon, R. S., Matthews, P. M., et al. (1999). Dissoci-ating pain from its anticipation in the human brain.Science, 284, 1979–1981.

Porro, C. A. (2003). Functional imaging and pain: Behav-ior, perception, and modulation. The Neuroscientist, 9,354–369.

Price, D. D. (2000). Psychological and neural mechanismsof the affective dimension of pain. Science, 288,1769–1772.

Price, D. D., Greenspan, J. D., & Dubner, R. (2003).Neurons involved in the exteroceptive function ofpain. Pain, 106, 215–219.

Rainville, P., Duncan, G. H., Price, D. D., et al. (1997).Pain affect encoded in human anterior cingulate butnot somatosensory cortex. Science, 277, 968–971.

Timmermann, L., Ploner, M., Haucke, K., et al. (2001).Differential coding of pain in the human primary andsecondary somatosensory cortex. Journal of Neuro-physiology, 86, 1499–1503.

Functional Imaging of DescendingModulation

▶Descending Circuits in the Forebrain, Imaging

Functional Loss

Definition

Functional loss is a decrease or loss of physiolog-ical function.

Cross-References

▶Disability, Upper Extremity

Functional Magnetic ResonanceImaging

Synonyms

fMRI

Definition

Functional Magnetic Resonance Imaging (or

fMRI) is the use of MRI to learn which regionsof the brain are active in a specific cognitive

task or during sensory stimulation, e.g. during

a pain experiment. It is one of the most recentlydeveloped forms of brain imaging, and mea-

sures hemodynamic signals related to neural

activity in the brain or spinal cord of humansor other animals. As nerve cells “fire” impulses,

they metabolize oxygen from the surrounding

blood. Approximately 6 s after a burst of neuralactivity, a hemodynamic response occurs and

that region of the brain is infused with oxygen-

rich blood. As oxygenated hemoglobin isdiamagnetic, while deoxygenated blood is

paramagnetic, MRI is able to detect a small

difference (a signal of the order of 3 %)between the two. This is called a blood-oxy-

gen-level-dependent, or “BOLD,” signal. The

precise nature of the relationship between neu-ral activity and the BOLD signal is a subject of

current research.

Cross-References

▶Amygdala, Functional Imaging

▶Cingulate Cortex, Functional Imaging▶Descending Circuits in the Forebrain, Imaging

▶Human Thalamic Response to Experimental

Pain (Neuroimaging)▶Nociceptive Processing in the Nucleus

Accumbens, Neurophysiology and Behavioral

Studies▶ Pain Processing in the Cingulate Cortex,

Behavioral Studies in Humans

▶ PET and fMRI Imaging in Parietal Cortex (SI,SII, Inferior Parietal Cortex BA40)

▶Thalamus and Visceral Pain Processing

(Human Imaging)▶Thalamus, Clinical Pain, Human Imaging

▶Thalamus, Clinical Visceral Pain, Human

Imaging

F 1328 Functional Imaging of Descending Modulation

Functional Magnetic ResonanceImaging (fMRI)

▶Amygdala, Functional Imaging

Functional Restoration

Definition

Functional restoration is a pain managementapproach geared specifically for chronic low

back pain patients. This approach places a strong

emphasis on function, and combines a quantita-tively directed exercise progression with disability

management and psychosocial interventions such

as individual and group therapy.

Cross-References

▶ Psychological Treatment of Chronic Pain,

Prediction of Outcome

Functional Restoration Program

▶Multidisciplinary Pain Centers, Rehabilitation

Functional Restoration/ExercisePrograms

▶ Physical Conditioning Programs

Functioning

▶ Functioning and Disability Definitions▶ Physical Exercise

Functioning and DisabilityDefinitions

Reuben Escorpizo and Gerold Stucki

Swiss Paraplegic Research, Nottwil, Switzerland

Department of Health Sciences and HealthPolicy, University of Lucerne, Lucerne,

Switzerland

ICF Research Branch in cooperation with theWorld Health Organization (WHO)

Collaborating Centre for the Family of

International Classifications in Germany,Nottwil, Switzerland

Synonyms

Classification; Disability; Functioning; ICD; ICF

Definition

Functioning; Disability; ICF; Classification; ICD

Introduction

The International Classification of Functioning,

Disability and Health (ICF) (WHO 2001)

was intended by the WHO to be the commonreference framework to describe the full spec-

trum of human functioning and disability. Asa conceptual model and a classification system,

the ICF can be applied in various ways in clinical

care, health and social policy, and research, andfor epidemiological and population surveys. The

ICF can be used to understand health and health-

related domains and compare data across regionsand countries, and as a system of coding (WHO

2001). The ICF can be applied regardless of the

setting, culture, and context.As a conceptual model, the ICF illustrates the

interrelationship between a health condition and

its impact on the individual’s body (body func-tions and body structure), and activities and

Functioning and Disability Definitions 1329 F

F

participation (societal impact). This relationship

may be influenced by environmental factors and

personal factors (Fig. 1).

Characteristics

The current framework of functioning and dis-

ability is the ICF (WHO 2001), in which disabil-ity is determined by impairment of body

structures and body functions, activity limita-

tions, and participation restrictions. Historically,there have been two major conceptual frame-

works in the field of disability: the International

Classification of Impairment, Disability andHandicap (ICIDH), which is the precursor to the

ICF, and the “functional limitation,” or Nagi,

framework (Nagi 1964). In the ICIDH (WHO1980), the four concepts were disease, impair-

ment, disability, and handicap. In the Nagi frame-

work, the four concepts were pathology,impairment, functional limitation, and disability.

Different from the ICIDH, the Nagi framework

was not accompanied by a classification. Build-ing on the conceptual frameworks of the ICIDH

and Nagi, the US Committee on a National

Agenda for the Prevention of Disabilities devel-oped a model emphasizing the interaction

between the disabling process, quality of life,

and individual risk factors (Pope and Tarlov1991).

The ICF attempts to achieve a synthesis and

integration of the different perspectives of health

from biological, psychological, and social per-spectives (i.e., biopsychosocial approach). It

emphasizes health-related “building blocks” ordomains to form specific disability models in

the context of health. The ICF has addressed

many of the criticisms of prior conceptual frame-works (e.g., lack of environmental consideration,

purely biomedical perspective), and has been

developed in a worldwide and comprehensiveexpert consensus process. For all these reasons,

the ICF is the generally accepted conceptual

framework and classification to describea persons’ level of functioning and disability in

light of his or her health condition. Disabilityserves as an umbrella term for impairments,activity limitations, and participation restrictions.

So it can be seen as the negative term of func-

tioning. The interaction of disability and healthcondition works in both directions, because the

presence of disability may evenmodify the health

condition. The level of disability may be indi-cated for body functions, body structures, activi-

ties and participation, and environmental by

using the generic ICF qualifiers of the WHO(WHO 2001). More information on the qualifiers

is provided later.

It is important to recognize that the ICF canserve as a common language (Stucki et al. 2002),

in that the texts that can be created with it (ICF)

can be used by different users, within theirintended purpose, and their scientific orientation.

The understanding of bidirectional interactions

and relationships between the components ofthe ICF is shown in Fig. 1.

Health condition refers to any kind of disorder,

illness, or disease. It may include informationabout pathogeneses and/or etiology. There are

(possible) interactions with all or any of the com-

ponents of functioning, namely, ▶ body func-tions and body structures, activities, and

participation (WHO 2001).

Body functions are the physiological (and psy-chological) functions of body systems. ▶Body

structures are anatomical parts of the body. Prob-

lems in body functions and body structures arecalled impairments, which are defined as

a significant deviation or loss (e.g., deformity)

of structures (e.g., joints), and/or functions

Health condition(disorder or disease)

Activities ParticipationBody Functions and Structures

EnvironmentalFactors

PersonalFactors

Functioning and Disability Definitions,Fig. 1 Interactions between the components of ICF

F 1330 Functioning and Disability Definitions

(e.g., reduced range of motion (ROM), muscleweakness, pain, or fatigue).

Activity is described as the execution of a taskor action by an individual. Difficulties an individ-

ual may have in executing activities are called

activity limitations (e.g., limitations in mobilitysuch as walking, climbing steps, grasping, or

carrying).

Participation is described as involvement ina life situation (i.e., societal involvement). It

represents the societal perspective of function-

ing. Problems an individual may experience ininvolvement in life situations are called partic-

ipation restrictions. Limitations and restrictions

are assessed against a generally accepted popu-lation standard. “Participation” records discor-

dance between the observed performance and

the expected performance. The expected perfor-mance is the population norm, which represents

the experience of people without the specific

health condition (e.g., with associated restric-tions in community life, recreation, and

leisure).

A person’s functioning (and disability) is con-ceived as a dynamic interaction between health

conditions (diseases, disorders, injuries, traumas,

etc.) and contextual factors. Likewise, there are(possible) interactions with all components of

functioning and contextual factors.

Contextual factors are factors that constitutethe context of an individual’s life, and in partic-

ular, the backgrounds against which health states

are classified in the ICF. There are two sets ofcontextual factors: ▶Environmental factors and

personal factors.

Environmental factors refer to all aspects ofthe external or extrinsic world that form the con-

text of an individual’s life and, as such, may have

an impact on that person’s functioning. Environ-mental factors include the physical world and its

features, the human-made physical world, other

people in different relationships and roles, atti-tudes and values, social systems and services, and

governing policies, rules, and laws.

ICF qualifiers can be assigned to rate the prob-lem for each domain under the ICF components

on body functions, body structures, activities and

participation, and environmental factors (Table 1).

In the case of environmental factors, the extent ofbeing a barrier or a facilitator is used.

Personal factors are contextual factors that

relate to the individual such as age, gender,social status, life experiences, lifestyle, habits,

coping styles, education, behavior, and other

personal characteristics. Risk factors could bedescribed under personal factors (e.g., lifestyle,

coping mechanism) or environmental factors

(e.g., living and work conditions, architecturalbarriers) that are associated with conditions such

as pain. Bidirectional arrows in Fig. 1 indicate

the possibility of feed forward and feedbackprocess. Risk factors also affect the progression

of disability and, may include, depending on the

stage, treatment, rehabilitation, age of onset,financial resources, healthcare provision, expec-

tations, and environmental barriers. Personal

factors are defined and included in the ICFmodel, but not yet classified (hence, it has no

categories nor qualifiers) into a coding system

like the rest of the components.The ICF is intended for use in multiple sectors

that include health, education, insurance, labor,health and disability policy, etc. In the clinical

Functioning and Disability Definitions, Table 1 ICFqualifiers

ICF qualifierEquivalentpercentage

Body functions, body structures, andactivities and participation

0 NO problem (none, absent, negligible, etc.) 0–4 %

1 MILD problem (slight, low, etc.) 5–24 %

2MODERATE problem (medium, fair, etc.) 25–49 %

3 SEVERE problem (high, extreme, etc.) 50–95 %

4 COMPLETE problem (total, etc.) 96–100 %

Environmental factors

+4 Complete facilitator 96–100 %

+3 Substantial facilitator 50–95 %

+2 Moderate facilitator 25–49 %

+1Mild facilitator 5–24 %

0 Neither barrier nor facilitator 0–4 %

1 Mild barrier 5–24 %

2 Moderate barrier 25–49 %

3 Severe barrier 50–95 %

4 Complete barrier 96–100 %

Functioning and Disability Definitions 1331 F

F

Functioning and Disability Definitions, Table 2 ICFcategories of the comprehensive ICF Core Set for chronicwidespread pain (brief core set marked with *)

ICF category(code) Title

Body functions

Global mental functions

b122 Global psychosocial functions

b126 Temperament and personality functions

b130* Energy and drive functions

b134* Sleep functions

Specific mental functions

b140 Attention functions

b147* Psychomotor functions

b152* Emotional functions

b1602* Content of thought

b164 Higher-level cognitive functions

b180 Experience of self and time function

Additional sensory functions

b260 Proprioceptive function

b265 Touch function

b270 Sensory function related to temperatureand other stimuli

b280* Sensation of pain

Functions of the haematological and immunologicalsystems

b430 Haematological system functions

Additional functions and sensations of the cardiovascularand respiratory systems

b455* Exercise tolerance functions

Genital and reproductive functions

b640 Sexual functions

Functions of the joints and bones

b710 Mobility of joint functions

Muscle functions

b730* Muscle power functions

b735 Muscle tone functions

b740 Muscle endurance functions

Movement functions

b760* Control of voluntary movementfunctions

b780 Sensations related to muscles andmovement functions

Body structures

s770 Additional musculoskeletal structuresrelated to movement

Activities and participation

Applyingknowledge

d160 Focusing attention

d175* Solving problems

(continued)

Functioning and Disability Definitions, Table 2(continued)

ICF category(code) Title

General tasks and demands

d220 Undertaking multiple tasks

d230* Carrying out daily routine

d240* Handling stress and other psychologicaldemands

Changing and maintaining body position

d410 Changing basic body position

d415 Maintaining a body position

Carrying, moving, and handling objects

d430* Lifting and carrying objects

Walking andmoving

d450* Walking

d455 Moving around

Moving around using transportation

d470 Using transportation

d475 Driving

Self-care

d510 Washing oneself

d540 Dressing

d570 Looking after one’s health

Acquisition of necessities

d620 Acquisition of goods and services

Householdtasks

d640* Doing housework

Caring for household objects and assisting others

d650 Caring for household objects

d660 Assisting others

General interpersonal interactions

d720 Complex interpersonal interactions

Particular interpersonal interactions

d760* Family relationships

d770* Intimate relationships

Work andemployment

d845 Acquiring, keeping and terminating ajob

d850* Remunerative employment

d855 Non-remunerative employment

Community, social and civic life

d910 Community life

d920* Recreation and leisure

Environmental factors

Products and technology

e1101* Drugs

(continued)

F 1332 Functioning and Disability Definitions

context, it is intended for use in needs assessment

andmatching interventions to specific health states,rehabilitation program, and outcome evaluation.

The joint use of the ICF and the International Clas-

sification of Diseases (ICD) needs to be addressedwhen applying the ICF in medicine in general

(Kostanjsek et al. 2011a, b) and pain rehabilitation

in particular. The WHO considers the ICF and theICD to be distinct but complementary classifica-

tions. According to this view, patient functioning

and health are associated with a condition or dis-ease, but are not merely and necessarily

a consequence of it. However, with the hundreds

of codeswithin the ICF, the ICF needs to be tailoredin order to be practical. Hence, for practical pur-

poses, short lists of ICF categories called ICF CoreSets have been developed (www.icf-research-

branch.org/home.html) and are relevant toa number of health conditions with a high burden,

including chronic widespread pain, i.e., pain inseveral regions of the body (Cieza et al. 2004a).

ICF Core Sets have also been developed for several

other conditions that may have pain as a commondenominator, including low back pain (Cieza et al.

2004b), ankylosing spondylitis (Boonen et al.

2010), osteoarthritis (Dreinhofer et al. 2004), andrheumatoid arthritis (Stucki et al. 2004). Table 2

shows the ICF Core Set for chronic widespread

pain (Cieza et al. 2004a). A comprehensive versionof the ICF Core Set includes the ICF categories

(units of domains) considered relevant for

a comprehensive multidisciplinary assessmentsuch as inhospital settings. The brief version of an

ICF Core Set, marked with an asterisk (*) in the

table, includes those ICF categories to be assessedin every clinical study and clinical encounter to

allow for a meaningful description of a patient’s

functioning and health. A practical demonstrationof how to use the ICF is shown in Fig. 2.

Current Measures in Pain Can Be Linkedto the ICFThere are measures available, generic or condition

specific, that can be linked to the ICF according tothe domains that these measures cover. The con-

cepts contained in such measures can be linked to

the ICF using defined linkage rules (Cieza et al.2005). For example, low back pain can be linked

to the body function domain of the ICF, and

other measures that assess pain and depressionin relation to activities of daily living can be

linked to the activities and participation domains

of the ICF. The linking can be made more specificto the category level (e.g., b280 for sensationof pain).

It is important to recognize that different mea-sures address different components of the ICF,

and it seems that the concepts contained in these

measures are generally represented in the ICF(Weigl et al. 2003). Condition-specific measures

typically focus on body functions and activities,

while generic measures tend to cover activitiesand participation including aspects of physical,

mental, and social health. Contextual factors are

hardly covered by any of these instruments.

Functioning and Disability Definitions, Table 2(continued)

ICF category(code) Title

Support and relationships

e310* Immediate family

e325 Acquaintances, peers, colleagues,neighbors, and community members

e355* Health professionals

Attitudes

e410* Individual attitudes of immediate familymembers

e420 Individual attitudes of friends

e425 Individual attitudes of acquaintances,peers, colleagues, neighbors, andcommunity members

e430 Individual attitudes of people inpositions of authority

e450 Individual attitudes of healthprofessionals

e455 Attitudes of other professionals

e460 Societal attitudes

e465 Social norms, practices, and ideologies

Services, systems, and policies

e570* Social security services, systems, andpolicies

e575 General social support services,systems, and policies

e580 Health services, systems, and policies

e590 Labor and employment services,systems, and policies

Functioning and Disability Definitions 1333 F

F

Nonetheless, there is a need to address all com-

ponents when assessing functioning and health in

patients with chronic health conditions (Ewertet al. 2004).

Finally, it is important to note that the perspec-

tive of functioning, disability, and health is differentwhen viewed from a medical versus functioning-

oriented perspective, e.g., in rehabilitation. From

the medical perspective, functioning and healthare seen primarily as a consequence of a disease

or condition. Accordingly, medical interventions

are targeted toward mitigation or elimination ofthe disease process. From a broader view, the mea-

surement of functioning, disability, and health is

required to evaluate patient-relevant outcomes ofan intervention. Hence, from a functioning-oriented

or rehabilitation perspective as depicted in the ICF,patients’ functioning and health are associated

with, but not merely a consequence of, a condition

or disease. Furthermore, functioning and health are

not only seen in association with a condition, butalso in associationwith personal and environmental

factors. Therefore, themeasurement of functioning,

disability, and health is relevant to evaluateintervention outcomes and for the diagnosis

(assessment) and overall clinical care. For the man-

agement of patients with pain conditions, consider-ation of the individual’s functioning is becoming

more and more critical than before.

Summary

In summary, the ICF can be used as a conceptual

framework and classification system to examine

and understand the impact and relation of pain

Activities

walking

standing

Participation

cannot go to university (study)

reduction of pain to enable resumption ofhigher education

Primary goal of rehabilitation:

cannot visit friends

cannot play soccer

sitting

bendingirritation of neuromeningealstructures

shortening of pelvic belt muscles

increased muscle tone of pelvic beltespecially of m. piriformis

iliosacral joint dysfunction

walking / standing

Environmental: lives in fourth floor flat; no elevator; lack of concentration due to medication

Personal: highly motivated for exercising

Body- Structures/Functions

reduced mobility of theleft leg

low back painpain in left leg

low back painMedical diagnosis:Name: Mr. Johnson

Age: 24

Hea

lth p

rofe

ssio

nal p

ersp

ectiv

e P

atie

nt p

ersp

ectiv

e

Contextualfactors:

Functioning and Disability Definitions,Fig. 2 Illustration of how the ICF components can beused to structure patient problems (listed in the uppersection “patient perspective”) as well as findings, andobservations by the rehabilitation team (listed in thelower section “health professional perspective”). Linesbetween the selected target problems from the patient’s

perspective (circled in the upper section, i.e., “walking/standing”), impaired body functions, and structures aswell as the given personal and environmental factors(in the lower section) denote their hypothesized associa-tive relationship. Note that the wording denotes patient’swords or special medical terms which can be linked backto specific domains of the ICF

F 1334 Functioning and Disability Definitions

with regard to the functioning and disability ofan individual. The ICF provides a holistic

biopsychosocial perspective that is beyond thetraditional biomedical model and, hence, can aid

in the thought process to guide clinical decision

making and clinical care in the context of painand pain-related conditions.

Acknowledgment Previous edition of this entry waswritten by Gerold Stucki and Thomas Ewert.

References

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Cieza, A., Stucki, G., Weigl, M., Kullmann, L., Stoll, T.,Kamen, L., Kostanjsek, N., & Walsh, N. (2004a). ICFCore Sets for chronic widespread pain. Journal ofRehabilitation Medicine, (44 Suppl.), 63–68.

Cieza, A., Stucki, G.,Weigl, M., Disler, P., J€ackel,W., vander Linden, S., Kostanjsek, N., & de Bie, R. (2004b).ICF Core Sets for low back pain. Journal of Rehabil-itation Medicine, (44 Suppl.), 69–74.

Cieza, A., Geyh, S., Chatterji, S., Kostanjsek, N., Ust€un, B.,& Stucki, G. (2005). ICF linking rules: An update basedon lessons learned. Journal of Rehabilitation Medicine,37(4), 212–218.

Dreinhofer, K., Stucki, G., Ewert, T., Huber, E.,Ebenbichler, G., Gutenbrunner, C., Kostanjsek, N., &Cieza, A. (2004). ICF Core Sets for osteoarthritis. Jour-nal of Rehabilitation Medicine, (44 Suppl.), 75–80.

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Kostanjsek, N., Rubinelli, S., Escorpizo, R., Cieza, A.,Kennedy, C., Selb, M., Stucki, G., & €Ust€un, T. B.(2011b). Assessing the impact of health conditionsusing the ICF. Disability and Rehabilitation, 33(15–16), 1475–1482.

Nagi, S. Z. (1964). A study in the evaluation of disability andrehabilitation potential:Concepts,methods, andprocedures.The American Journal of Public Health, 54, 1568–1579.

Pope, A. M., & Tarlov, A. R. (1991). Disability inAmerica: Toward a national agenda for prevention.Washington, DC: National Academy Press.

Stucki, G., Ewert, T., & Cieza, A. (2002). Value andapplication of the ICF in rehabilitation medicine. Dis-ability and Rehabilitation, 24, 932–938.

Stucki, G., Cieza, A., Geyh, S., Battistella, L., Lloyd, J.,Symmons, D., Kostanjsek, N., & Schouten, J. (2004).ICF Core Sets for rheumatoid arthritis. Journal ofRehabilitation Medicine, (44 Suppl.), 87–93.

Weigl, M., Cieza, A., Harder, M., et al. (2003). Linkingosteoarthritis specific health status measures to the inter-national classification of functioning, disability andhealth (ICF). Osteoarthritis and Cartilage, 11, 1–5.

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WHO. (2001). International classification of functioning,disability and health: ICF. Geneva: WHO.

Funiculus

Definition

Longitudinal subdivisions of the spinal whitematter that are named according to their location

within the spinal cord.

Cross-References

▶ Spinothalamic Projections in Rat

Funiculus 1335 F

F