Pandora’s SuBOXone®: Can it treat chronic pain in opioid use disorder?

Pharmacotherapy Grand Rounds Leila Petok, Pharm.D.

PGY-2 Pain Management & Palliative Care Pharmacy Resident South Texas Veterans Health Care System

The University of Texas College of Pharmacy University of Texas Health Science Center San Antonio

Learning Objectives

1. Describe chronic pain and its pathophysiology2. Review criteria for opioid use disorder and medications for treatment3. Evaluate available evidence for buprenorphine/naloxone treatment of chronic pain in opioid use disorder

Speaker Disclosure: Dr. Leila Petok has indicated that she has no relevant financial relationships to disclose relative to the content of her presentation.

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PAIN I. Background 1. Epidemiology & Economic Burden1-2

a. Pain accounted for 5 out of top 10 conditions responsible for most years lived with disability between 1990 -2010 b. In 2016, an estimated 20.4% of U.S. adults (50 million) had chronic pain c. Total costs of chronic pain ranged from $560 billion - $635 billion in 2010; compare to annual costs of heart

disease ($309 billion), cancer ($243 billion), and diabetes ($188 billion) 2. Definition3-4

a. “An unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage”

i. Is complex and always includes subjectivity ii. Contains sensory, emotional, cognitive, and social components

3.. Classifications5-7

Figure 1. Pain Classifications

Table 1. Pain Classifications Type of Pain Definition Example

Classified by Time

Acute Short-term pain that lasts < 3 months, a physiological response to adverse chemical, thermal, or mechanical stimuli; a warning signal for physical injury that is generally self-limiting

Hand on stove, chemical burn, broken bone

Chronic

Intractable pain that lasts ≥ 3 months, a progression from acute pain with biopsychosocial contributions and changes that contribute to an overall “pain experience”; ongoing warning signals in absence of noxious stimuli that does not typically resolve on its own

Fibromyalgia, Complex Regional Pain Syndrome (CRPS), chronic low back pain (CLBP), phantom limb pain

Nociceptive Pain

Somatic From nociceptors in bone, peripheral soft tissue, joints, muscles; usually well-localized; aching, stabbing, sharp, dull

Sprains, strains, lacerations, arthritis, tendonitis

Visceral

From nociceptors in the thoracic, pelvic, or abdominal organs; diffuse/poorly localized, referred to other locations, accompanied by motor and autonomic reflexes (nausea and vomiting); deep, squeezing, sharp, dull

Appendicitis, angina, menstrual cramps, nephrolithiasis, chronic pancreatitis

Non-nociceptive pain

Neuropathic Resulting from injury to neural structures within peripheral or central nervous system; usually sharp, burning, tingling

Post-herpetic neuralgia, diabetic neuropathy, sciatica

Psychogenic Pain attributable to primarily psychological factors in absence of objective physical pain pathology; poorly understood

Conceivably any pain that occurs in the body (ex. headache, back pain)

Pain

Acute

Visceral Somatic

Chronic

Non-nociceptive

Neuropathic

Periperhal Central

Psychogenic

Nociceptive

Visceral Somatic

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4. Pathophysiology3,8

a. Ascending (Excitatory) Pathway i. First order neuron: periphery à peripheral nerve à dorsal horn of spinal cord

ii. Second order neuron: dorsal horn à cross over to contralateral side à ascend spinal cord to thalamus iii. Third order neuron: thalamus à terminate in cerebral cortex

b. Descending (Inhibitory) Pathway i. Cerebral cortex à periaqueductal grey matter à Nucleus Raphe Magnus à dorsal horn of spinal cord à

inhibition of ascending pathway ii. Pain cessation results from pre-and post-synaptic inhibition, with contribution from serotonin,

noradrenergic, gamma-Aminobutyric acid (GABA), and opioid receptor activity

Source: Mattox KL, Moore EE, Feliciano DV: Trauma, 7th ed: www.accesspharmacy.com

Figure 2. Ascending Pain Pathway

II. Chronic Pain

1. Etiology9-11

a. “Chronification” of pain – the progression from acute pain to established chronic pain b. Neuroplasticity - capacity of the nervous system to modify itself in response to experience and injury c. Central sensitization – an abnormal state of responsiveness or increased gain of the nociceptive system due to

changes in the central nervous system (CNS) i. Pain pathways undergo a functional shift from high-threshold nociception to low-threshold

hypersensitivity Ascending pathway: increased membrane excitability and progression of synaptic strength Descending pathway: decreased inhibitory transmission

ii. Allodynia – perception of pain from non-noxious stimuli (ex. gentle breeze, softly brushing hair) iii. Hyperalgesia – abnormally increased pain experienced from a pain-causing stimulus

d. Overall shift from nociceptive pathways to emotional pathways contributes to a “chronic pain experience” i. Allostasis – the process of physiological systems achieving stability through change when confronted

with a recurrent stimulus or stressor i. Persistent pain leads to cumulative strain and changes in in normative psychological processes such as

perception, emotion, cognition, and motivation

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Table 2: Factors Associated with Chronic Pain Development9,11-12 Demographic Psychological Medical Comorbidities

• Older age • Female gender • Lower education level • Smoking • Overweight • Disability • Worker’s compensation • Higher work dissatisfaction • Higher physical work demand

• History of sexual abuse • Social rejection/isolation • Maladaptive coping • Pain catastrophizing • Fear avoidance • Trauma/PTSD • Depression, anxiety • Bipolar Disorder • Personality Disorder • History of/active substance abuse

• Poor overall health, multimorbidity

• Surgical history • CHF • COPD • Cancer • Critical illness recovery

(ex. heart attack, stroke) • TBI/concussions • Sleep disorders

PTSD = post-traumatic stress disorder; CHF = congestive heart failure; COPD = chronic obstructive pulmonary disease; TBI = traumatic brain injury

2. Chronic Pain and Mental Health11-13 a. Comorbid Depression

i. Prevalence ranges 2-61% across all pain groups ii. > 50% in fibromyalgia, temporomandibular joint disorder, chronic spinal pain, chronic abdominal pain

iii. > 20% in arthritis, migraine headache, pelvic pain b. Comorbid Anxiety and PTSD

i. Prevalence ranges 1-10% for Generalized Anxiety Disorder (GAD) and 1-23% PTSD ii. > 50% in fibromyalgia, temporomandibular joint disorder, chronic abdominal pain

iii. > 35-40% in arthritis, migraine headache, pelvic pain c. Substance Use Disorders (SUDs)

i. Across all pain groups, prevalence of alcohol abuse/dependence ranges 2%-22%; combined prevalence of drug abuse, drug dependence, or any SUD ranges 1% - 25%.

ii. Highest with fibromyalgia, chronic spinal pain, arthritis iii. In adults with chronic pain on long-term opioid therapy, estimated prevalence of OUD ranges 1-23% iv. Those with chronic pain are 2-3 times more likely to develop SUD than those without chronic pain, and

those with SUD are 1.5 times more likely to develop chronic pain

III. Non-Opioid Treatment Options14-16

Table 3. Non-Pharmacologic Treatment Options Treatment Description & Mechanism Utility

Acupuncture Insertion of fine needles through skin at specific points; ancient Chinese practice with various hypotheses for pain relief such as increased blood flow and modulation of pain neurotransmitters

May be beneficial for headache, musculoskeletal pain, osteoarthritis

Manipulation Manipulation –high-velocity low-amplitude movements to push a joint beyond its normal range of movement; may relieve joint pressure or stimulate nerve fibers that inhibit pain transmission

May increase mobility and reduce joint pain, back pain, and neck pain

Traction Manual (therapist) or mechanical (devices) techniques to steadily or intermittently “pull” neck or spine; opens joint spaces to relieve pressure on nerve roots, may relax muscles

May reduce cervical or lumbar pain, not for acute low back pain

Transcutaneous Nerve Stimulation

(TENS)

Electrical current passed through electrodes on skin with increasing intensity via frequency (Hz); inhibits pain signaling and stimulates endorphins

May help labor pain, joint pain, neck & back pain, fibromyalgia, neuropathy

Laser Therapy

Hand-held laser device placed over a painful or injured area of the body; Cold/low-level lasers < 500 milliwatts (mw) in power; High-power lasers > 500 mw; may decrease nerve sensitivity by decreasing bradykinin and increasing endorphins

May accelerate tissue repair and healing

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Heat Therapy Heating pad, sauna, steam room, hot packs; muscle relaxation and increased blood flow with effects seen at a depth of 1-2 cm

Reducing muscle spasm and stiffness, improving flexibility

Cryotherapy Ice packs, baths, cold cuffs, or other devices; temporarily reduces nerve activity and decreases blood flow

Reduce inflammation, local metabolism, and acute pain

Exercise Physical therapy, occupational therapy, resistance training, strengthening, aerobic, stretching, mobilization (moving joint within normal range)

Improves range, strength, flexibility, mood, and increases pain tolerance

Interventional Procedures

Procedures that may include neural blockade or ablation, nerve stimulation, repair surgery, steroid injections, intrathecal drug delivery systems

Directly target injury or area of pain to block or minimize pain

Psychotherapy Pain psychology, psychotherapy, cognitive behavioral therapy (CBT); addressing psychosocial contributors to pain with help to alleviate pain suffering and enhance coping skills

Improve function, reduce fear/anxiety

Table 4. Non-Opioid Pain Medications

NSAIDS Diclofenac Ibuprofen Indomethacin

Ketorolac Meloxicam Nabumetone

Naproxen Piroxicam Sulindac

Antidepressants Venlafaxine Duloxetine

Amitriptyline Milnacipran Tricyclics

Anticonvulsants Lamotrigine Topiramate Oxcarbazepine

Mexiletine Carbamazepine Divalproex

Gabapentin Pregabalin

Muscle Relaxants Baclofen Cyclobenzaprine Carisoprodol

Methocarbamol Metaxalone

Tizanidine Benzodiazepines

Topicals Counter-irritants (e.g. Icy Hot®) Topical NSAIDs (e.g. diclofenac)

Local anesthetics (e.g. lidocaine) Capsaicin

Others Acetaminophen Ketamine Aspirin NSAIDs = Nonsteroidal anti-inflammatory drugs

IV. Opioids 1. Receptors17

a. Opioid receptors are 7-transmembrane G-protein coupled receptors b. Decrease adenyl cyclase production of the secondary messenger cyclic adenosine monophosphate (cAMP) c. Inhibition of voltage-gated calcium (Ca2+) channels causes a decrease in Ca2+ influx d. Results in activation of potassium channels and overall membrane hyperpolarization e. Hyperpolarized state inhibits release of neurotransmitters such as glutamate and substance P, which in turn

inhibits pain transmission

2. Receptor Subtypes18-20 a. Opioid receptors mediate analgesia but also have nuanced functions and effects due to variable regional

expression, plasticity, and locations in central and peripheral organ systems b. Mu (MOR) – primary target for opioid analgesics; mediates respiratory depression, sedation, reward/euphoria,

nausea, urinary retention, biliary spasm, pruritis, and constipation; binds endogenous β-endorphin c. Kappa (KOR) – mediates dysphoric, aversive, sedative, and diuretic effects; binds endogenous dynorphin d. Delta (DOR) – mediates reward, respiratory depression, and convulsions; agonists have anxiolytic and

antidepressant activity; binds endogenous enkephalin e. Opioid-Receptor-Like 1 receptor (ORL1) – contributes to analgesia; binds endogenous nociception

3. Opioids by Classification19,21 a. Full agonist – binds to and activates a receptor

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b. Partial agonists – binds to and activates a receptor, but only partially relative to a full agonist c. Mixed agonist/antagonist – acts as a full-agonist at some receptors and antagonist at other receptors d. Antagonists – bind to receptor but do not activate

Table 5. Opioid Medications By Classification

Full Agonist Codeine, fentanyl, heroin, hydrocodone, hydromorphone, levorphanol, meperidine, methadone, morphine, oxycodone, oxymorphone, tramadol

Partial Agonist Buprenorphine (MOR), butorphanol, pentazocine

Mixed Agonist/Antagonist Buprenorphine (antagonist at KOR, DOR), butorphanol, nalbuphine, pentazocine

Antagonist Naloxone, naltrexone

4. Considerations for Use a. Prior to 1980s, opioids were rarely used outside of severe acute pain, surgical pain, and cancer pain b. Increased prescribing trends occurred in the 1990s and 2000s with the opioid epidemic; current CDC guideline

advocates for opioid minimization c. Opioid-induced hyperalgesia (OIH) vs. tolerance22

i. OIH – nociceptive sensitization caused by exposure to opioids ii. Tolerance – progressively reduced response to a drug or substance with repeated use

d. Common adverse effects: cognitive impairment, constipation, sexual dysfunction, hypogonadism, nausea/vomiting, orthostatic hypotension, sedation/somnolence

e. Serious adverse effects: opioid-induced respiratory depression, addiction

OPIOID USE DISORDER (OUD) 1. Definition23-24 – a pattern of use leading to clinically significant impairment or distress (DSM®)

Table 6. DSM® Criteria for Opioid Dependence, Opioid Abuse, and Opioid Use Disorder DSM-5® Criteria* for Opioid Use Disorder DSM-IV TR® Criteria* for Opioid Dependence

With ≥ 2 the following in a 12-month period:

1. Opioids often taken in larger amounts or duration than intended

2. Persistent desire/unsuccessful efforts to cut down or control opioid use

3. A great deal of time is spent obtaining, using, or recovering from effects of opioids

4. Craving / strong desire / urge to use opioids

5. Recurrent use resulting in failure to fulfill major role obligations at work, school, or home

6. Continued use despite social or interpersonal problems

7. Important social, occupational, or recreational activities given up or reduced because of use

8. Recurrent use in hazardous situations

9. Continued use despite knowledge of having a persistent physical or psychological problem likely to have been caused or exacerbated by opioids

10. Tolerancea

11. Withdrawalb

With ≥ 3 of the following in a 12-month period: 1. Tolerancea 2. Withdrawalb 3. Opioids often taken in larger amounts or duration than

intended 4. Persistent desire/unsuccessful efforts to cut

down/control use 5. A great deal of time is spent obtaining, using, or

recovering from effects of opioids 6. Important social, occupational, or recreational activities

given up or reduced because of use 7. Continued use despite knowledge of having a persistent

physical or psychological problem likely to have been caused or exacerbated by opioids

DSM-IV TR® Criteria for Opioid Abuse With ≥ 1 of the following in a 12-month period: 1. Recurrent use resulting in failure to fulfill major role

obligations at work, school, or home 2. Recurrent use in hazardous situations 3. Recurrent opioid-related legal problems (e.g., arrests

for disorderly conduct) 4. Continued use despite knowledge of having a persistent

physical or psychological problem likely to have been caused or exacerbated by opioids

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*Criteria not considered to be met for those individuals taking opioids solely under appropriate medical supervision. aDefined by either of the following:

• A need for markedly increased amounts of opioids to achieve intoxication or desired effect • A markedly diminished effect with continued use of the same amount of an opioid

bManifested by either of the following: • The characteristic opioid withdrawal syndrome • Opioids (or a closely related substance) are taken to relieve or avoid withdrawal symptoms

2. Differences from DSM-IV-TR® to DSM-5 a. Two separate diagnoses of substance abuse/dependence combined into one diagnosis of substance use disorder b. Only 1 symptom required for substance abuse, while DSM-5 requires ≥ 2 symptoms for substance use disorder c. “Legal problems” dropped in favor of cravings or a strong desire/urge to use a substance d. Three categories of disorder severity formed:

i. 2-3 symptoms = mild substance use disorder ii. 4-5 symptoms = moderate substance use disorder

iii. 6+ symptoms = severe substance use disorder

3. Epidemiology26-27 a. Boscarino et al.28 found similar a similar prevalence of lifetime prescription OUD among outpatients on opioid

therapy using criteria from both DSM versions i. Among 705 patients, prevalence was 34.9% with DSM-5 criteria (95% CI = 30.5-39.5) and 35.5% with

DSM-IV criteria (95% CI = 31.1-40.2) b. A 2015 review of 38 studies using DSM-5® criteria found prevalence of OUD among those on chronic opioid

therapy to be 8-12% (DSM-5® Criteria) c. A 2013 review of 17 studies with stricter inclusion criteria found median prevalence of opioid dependence to be

4.5% (range 0% - 32%, DSM-IV® Criteria)

2. Neurobiology of Addiction28 a. Cycle: drug taking à intoxication à development of tolerance à increased intake à physical discomfort,

somatic withdrawal during abstinence; potential for dysphoria during each step à drug taking b. Craving – intense preoccupation or desire to obtain or use a substance c. As substance use and severity of withdrawal effects escalate, there is decreased reward, increased “antireward”,

and sensitized stress response i. Decreased dopamine, opioid peptides, GABA, and glutamate in nucleus accumbens or amygdala

ii. Recruitment of norepinephrine, dynorphin, neuropeptide Y, and nociceptin iii. Increased corticotropin-releasing factor (CRF), adrenocorticotropic hormone (ACTH), and corticosterone

from the hypothalamic-pituitary-adrenal (HPA) axis d. Neurobiological changes that occur with repeated drug use shift reward-associated impulsivity to dysphoria-

reducing compulsivity e. Dysregulation may persist during abstinence as a “protracted withdrawal” and augments relapse susceptibility

4. Risk factors12,29 a. Prior history of opioid misuse b. Personal or family history of SUD c. Comorbid psychiatric disorders d. Current cigarette smoking e. Legal history f. History of trauma

g. Significant psychosocial stressors h. Younger age i. Female sex j. Lower socioeconomic status k. Unemployment

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Figure 4. Factors Associated with Developing Chronic Pain and OUD

5. Trends9,29-31

a. 21-29% of patients prescribed opioids for chronic pain misuse them i. Misuse – use without a prescription, a reason other than as directed by a physician, or in greater

amounts/more often/longer than prescribed b. Legal changes (state, federal), policy changes (third party payers, healthcare systems), and guideline updates

(CDC, VHA) have led to decreased opioid prescribing i. Iatrogenic addiction – caused inadvertently by medical treatment/healthcare practice itself; liberal opioid

prescribing precipitates addiction in previously non-addicted individuals c. Recent increases in heroin and illicit fentanyl use

i. Between 2005 and 2013, opioid initiation with prescription opioids among treatment-seeking heroin users decreased from 84% to 52%, while opioid initiation with heroin increased from 8.7% to 33%

ii. In this patient population, a diagnosis can be uncomplicated addiction, physical dependence, uncontrolled pain, or a combination of the three

6. Maintenance Treatments30,31 a. Methadone – Schedule II Controlled Substance

i. The most studied medication for OUD, shown to suppress illicit opioid use with better treatment retention than buprenorphine but has greater risk of physical dependence and potential for serious side effects

ii. Can only be dispensed through a Substance Abuse and Mental Health Services Administration (SAMHSA)-certified opioid treatment program (OTP)

iii. Adverse effects – increased risk of respiratory depression, increased QTc prolongation, dysphoria, disorientation, hypogonadism

iv. Stabilization doses ≥ 60mg associated with greater treatment retention; 80-120mg is typical daily range b. Naltrexone

i. Opioid antagonist, available as oral or long-acting injectable (LAI) ii. Moderate quality evidence supports use of long-acting injectable (LAI) for reduced opioid consumption

and improved patient retention iii. No abuse potential or physical dependence iv. Patients must be completely abstinent of all opioids prior to induction v. Adverse effects – irritability, nausea, vomiting, withdrawal syndrome, tachycardia

• Younger age • Family history of SUD • Legal history • Unemployment

• Female • Low socioeconomic status • Smoking • Mental health disorders • Pain catastrophizing • History of substance abuse • History of psychotropic

medication abuse • Psychological stress • History of sexual abuse • History of trauma

• Older age • Obesity • Disability • Worker’s comp • Physical work

demand • Work dissatisfaction • Multi-morbidity • Surgical history • Sleep disorders

Chronic Pain OUD

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BUPRENORPHINE I. Pharmacology28-29,32

1. MOR – high-affinity partial agonist a. Produces analgesia with only 5-10% of receptors occupied, with noted ceiling effect at doses > 32 mg b. Slow dissociation from mu receptor c. Can produce euphoria or respiratory depression, but effects are weaker than full opioid agonists d. Unique selectivity for arylepoxamide receptor (AEAr) which may contribute to analgesia based on rat studies

2. KOR – high affinity antagonist a. Anti-hyperalgesic activity (as hyperalgesia is likely the result of dynorphin upregulation) b. Antidepressant activity associated with KOR antagonism c. Less sedation and dysphoria compared to other opioids

3. DOR – antagonist 4. ORL-1 – low affinity partial agonist

a. May contribute to ceiling effect on analgesia 5. Buprenorphine to morphine equianalgesic ratio ranges 1:60 - 1:100 6. Enhanced Safety Profile

a. Less risk of QTc prolongation compared to methadone b. Less risk of respiratory depression and constipation than other opioid medications c. Not associated with monoamine reuptake or serotonin syndrome d. Doses adjustments not required for renal impairment or mild to moderate hepatic impairment (Child-Pugh Class

A and B) II. Formulations 1. FDA-Approved for Pain

a. Schedule III Controlled Substance – does NOT require X-DEA or special treatment setting to prescribe 2. FDA-Approved for Treatment of OUD

a. Schedule III Controlled Substance – To prescribe, a practitioner must obtain Controlled Substance Act Waiver (X-DEA number) by completing 8 hours of required training and an application to SAMHSA

i. The 2000 U.S. Drug Addiction Treatment Act, part of the Children’s Health Act, allows physicians prescribe schedule III, IV, and V drugs to manage addiction

ii. Limit maintenance therapy to 100 patients under a single physician iii. These formulations cab be prescribed off-label for pain, but prescription must clearly denote this

III. Pharmacokinetics32, 34-39 1. Oral bioavailability 10-15% due to first-pass metabolism, hence current formulations 2. Sublingual buprenorphine bioavailability = 50% parenteral buprenorphine bioavailability

Table 7. Formulations and Pharmacokinetics of Buprenorphine . Buprenorphine Formulations for Pain

Belbuca® (buccal film): 75, 150, 300, 450, 600, 750, 900 micrograms

Previous Dose (oral MMED) Belbuca® Starting Dose

< 30 75 mcg daily or q12h

30 – 89 150 mcg q12h

90 – 160 300 mcg q12h

Butrans® (transdermal patch): 5, 7.5, 10, 15, 20 micrograms / hour

Generic: 5, 7.5, 10, 15, 20 micrograms / hour

Previous dose (oral MMED) < 30 mg 30 – 80mg

Butrans® Starting Dose 5 mcg/hr 10 mcg/hr

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Buprenorphine Formulations for OUD Probuphine® (subcutaneous implant): 74.2 milligrams Sublocade® (pre-filled syringe): 100 mg/0.5 mL (0.5 mL); 300 mg/1.5 mL (1.5 mL) Subutex® (SL tablet, Canada): 2, 8 milligrams Generic: 2, 8 milligrams Suboxone® (buprenorphine/naloxone SL film or tablet): 2mg/0.5mg, 4mg/1mg, 8mg/2mg, 12mg/3mg Generic: 2mg/0.5mg, 4mg/1mg, 8mg/2mg, 12mg/3mg Bunavail® (buprenorphine/naloxone buccal film): 6.3/1mg, 4.2/0.7mg, 2.1/0.3mg Zubsolv® (buprenorphine/naloxone SL tablet): 0.7mg/0.18mg, 1.4mg/0.36mg, 2.9mg/0.71mg, 5.7mg/1.4mg, 8.6mg/2.1 mg, 11.4mg/2.9mg Generic: 2mg/0.5mg, 8mg/2mg

Buprenorphine and Morphine Equivalents32

Sublingual (mcg) Transdermal (mcg/hr) Morphine (mg/day) 240 5 12 480 10 24 960 20 48 1680 35 84 2520 52.5 126 3360 70 168

Pharmacokinetics of Sublingual & Buccal Buprenorphine Formulations

Butrans® Belbuca® Subutex® Bunavail® Zubsolv® + Suboxone®

Absorption • Steady state levels

achieved by day 3 • Heat: 26% - 55%

increase in blood concentrations that return to normal within 5 hours after heat removed

Absorption • Plasma levels

increase in linear fashion, absolute bioavailability 46 – 65%

• Steady-state levels achieved prior to 6th dose

Absorption • Plasma levels

increase with increasing doses

Absorption • Plasma levels

increase with increasing doses

Absorption • One Zubsolv 5.7

mg/1.4 mg tablet has equal buprenorphine exposure and 12% lower naloxone exposure compared to one Suboxone® 8 mg/2 mg tablet

Distribution: ~96% protein bound, primarily to alpha and beta globulin Metabolism: N-dealkylation by CYP3A4 to norbuprenorphine and glucoronidation by UGT-isoenzymes (mainly

UGT1A1 and 2B7) to buprenorphine 3β-O-glucuronide Excretion: Urine (30%) and feces (69%)

Elimination half-life • After removal,

concentrations decrease ~50% within 10-24 hours; terminal half-life ~26 hours

Elimination half-life • 27.6±11.2 hours

Elimination half-life • 31-35 hours

Elimination half-life • 16.4 to 27.5 hours • Naloxone 1.9-2.4

hours

Elimination half-life • 24 to 42 hours • Naloxone 2-12 hours

CNS clearance slower than plasma clearance, accounts for difference between half-life and duration of analgesia MMED = milligram morphine equivalent per day

2. Naloxone36,39

a. Short-acting opioid receptor antagonist co-formulated with buprenorphine as an abuse-deterrent b. Absorption

i. Bioavailability of SL buprenorphine (40%) is much higher than SL naloxone (10%) ii. If administered intravenously, rapid absorption occurs to precipitate an immediate opioid withdrawal

c. Distribution – ~45% protein bound, primarily to albumin d. Metabolism – hepatic via glucoronidation e. Elimination – plasma half-life 2-12 hours, excreted in urine

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IV. Efficacy for Chronic Non-Cancer Pain40-46

Table 8. Studies Investigating Buprenorphine for Chronic Non-Cancer Pain

Study Study Design Pain Type & Intervention

Primary Pain Outcome Other Results

Malinoff et al. 2005

Nonrandomized, open-label clinical trial (n=95)

CNCP • 4-16mg SL

divided daily dose

86% had moderate to substantial pain relief as rated by VAS

• 8% had opioid addiction • 6 withdrew due to SE or

worsening pain

Gordon et al 2010

Randomized, double-blind, placebo-controlled crossover study (n=78)

Moderate to severe CLBP • 10-40mcg/hr TD

every 7 days

Mean VAS score significantly lower with BUP compared to placebo (45.3 [21.3] vs 53.1 [24.3] mm, respectively; P = 0.022)

• BUP associated with significantly greater N/V, dizziness, somnolence, dry mouth, but not constipation

• 20.5% withdrew due to side effects

Gianni et al 2011

Multicenter, prospective, observational study in elderly patients (n=93)

CNCP (mainly OA) • 17.5mcg/hr – 70

mcg/hr TD; patch cut if lower dose needed

Pain ↓ by –56% (from 8.0 to 3.9 on VNRS)

• Mean age 79.7 years • No change in MMSE • 12.9% withdrew due to side

effects • Most common SE nausea,

constipation, sedation

Steiner et al. 2011 (A)

Multicenter, randomized, double-blind study in opioid-naïve patients (n=541)

Moderate to severe CLBP • 10-20 mcg/hr TD

every 7 days

Statistically sig. lower pain scores vs. placebo (least square mean treatment diff: -0.58, P=0.0104) for “average pain over last 24 hours”

• 86 centers in U.S. • Most common adverse

events were N/V • 16% withdrew due to side

effects, 9% withdrew due to lack of therapeutic effect

Steiner et al. 2011 (B)

Multicenter, randomized, double-blind, double-dummy, parallel group, active-controlled superiority study in opioid-experienced patients (n=433)

Moderate to severe CLBP • 5mcg/hr TD x7

days • 20mcg/hr TD x7

days • 40mg/day

oxycodone

“Average pain in last 24 hours’’ decreased −0.67 (20mcg/hr vs. 5mcg/hr, P<0.001) and −0.75 (oxycodone vs. 5mcg/hr, P<0.001)

• 75 centers in U.S. • Completion rates for the

BUP 5mcg, 20mcg, and oxy groups were 58, 67, and 72%; discontinuation rates due to lack of efficacy 24, 11, and 7%; discontinuation due to adverse events were 6, 13, and 7%, respectively

SL = sublingual; CNCP = chronic non-cancer pain; OA = osteoarthritis; TD = transdermal; BUP = buprenorphine, SE = side effects; CLBP = chronic low-back pain; VAS = visual analog scale; VNRS = verbal numeric rating scale; MMSE = Mini Mental State Examination; N/V = nausea and vomiting; sig. = significant; oxy = oxycodone

• The studies above show that buprenorphine at low doses (mcg) or high doses (mg) can be used to treat different types of chronic pain, including osteoarthritis and low back, and is safe for use in elderly patients

V. Efficacy for Treatment of Opioid Use Disorder / Opioid Dependence46-48

Table 9. Studies Investigating Buprenorphine for Treatment of Opioid Dependence Study Study Design Treatments Outcome Other Results

Fudala et al. 2003 Multicenter,

double-blind randomized, placebo-controlled trial (n=326)

Daily doses of: • BUP/NLX 16mg/4mg • BUP 16mg • Placebo

Proportion of urine samples neg for opiates greater in BUP/NLX (17.8%) and BUP (20.7%) vs. placebo (5.8%, P<0.001 for both groups)

• Trial terminated early because both BUP groups had greater efficacy than placebo; cocaine-positive samples did not differ significantly among groups

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Mattick et al. 2003

Randomized, controlled, double-blind, double-placebo parallel group trial (n=405)

BUP or methadone daily with flexible dosage regimen • Weeks 1–6: daily doses • Weeks 7–13: BUP patients

received double week 6 dose on alternate days up to max 32mg/day

• Max dose methadone 150mg/day

No sig. diff. in completion at 13 weeks (59% methadone, 50% BUP, Χ2 = 3.516, df = 1, P = 0.061); No sig. between-group diff. in morphine-positive urines or self-reported heroin use

• Week 13 average daily dose methadone 57.3mg, Week 13 average daily dose BUP 11.2mg

Fiellin et al. 2012

Single-site, open-label randomized clinical trial in patients with prescription opioid dependence (n=113)

Taper group: stabilized for 4 weeks on BUP then tapered 2-mg every 3 days x3 weeks Maintenance group: stable dose x14 weeks with option to increase to 20 and 24 mg/day

Mean percentage of urine samples neg for opioids was lower in taper group (35.2% [95%CI, 26.2%-44.2%]) vs. maintenance group (53.2%[95%CI, 44.3%-62.0%])

• Patients in taper group less likely to complete trial (6/57 [11%] vs 37/56 [66%]; P <.001); 16 patients in taper reinitiated BUP after taper due to relapse

BUP = buprenorphine; NLX = naloxone; neg = negative; sig. = significant; diff. = difference • The studies above show that buprenorphine therapy is efficacious in maintaining opioid abstinence at rates

comparable to methadone abstinence rates, and maintenance therapy with buprenorphine is more efficacious than planned taper to maintain opioid abstinence and treatment retention

CLINICAL QUESTION: Can buprenorphine/naloxone treat chronic pain in patients with opioid use disorder?

I. Neumann et al. (2013)

Table 10. A Preliminary Study Comparing Methadone and Buprenorphine in Patients with Chronic Pain and Coexistent Opioid Addiction49

Objective To compare methadone vs. BUP/NLX treatment on analgesia, illicit drug use, treatment retention, and functioning in patients with CNCP and co-existent opioid addiction in a primary care setting

Methods Design Randomized controlled trial of patients in a primary care setting (ClinicalTrials.gov NCT00879996)

Sample

• Telephone screen for chronic pain and prescription “drug addiction” followed by face-to-face interview • Chronic pain diagnosis confirmed by clinical examination and diagnostic imaging (e.g. X-rays, computed

tomography [CT] scan, magnetic resonance imaging [MRI])

Inclusion Exclusion • 18+ years old • Well-documented CNCP related to spine large joint

(e.g. hip, knee, shoulder) • Addiction to prescription opioids o Confirmed with Drug Abuse Screen Test (DAST)

score >4, and a 7-item checklist based on DSM-IV criteria for opioid dependence

Per ClinicalTrials.gov: • Live in Western New York State • Have health insurance/ability to pay for health care • Not a member of a vulnerable population (e.g.

pregnancy, prisoners) • No methadone or buprenorphine treatment in past year

• Homeless or on parole • Co-occurring psychiatric disorder (e.g.

schizophrenia) • Unable to give consent or lacked consent

from attending physician • EKG with prolonged QT interval or

previous cardiac/pulmonary issues • Taking medication contraindicated with

methadone or buprenorphine • Prior methadone or buprenorphine

maintenance treatment • Pregnant

Intervention • Participants randomized using 3:3 ratio, block randomization procedure to receive 6 months of either

1. (SL) BUP/NLX: 4/1mg - 16/4 mg in 1-4 divided daily doses (experimental group) 2. (PO) methadone: 10–60 mg in 3-4 divided daily doses (active comparator group)

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• Permitted to change to other study medication for inadequate pain relief, cravings, or side effects • Monthly follow-up appointments with mandatory urine samples for toxicology screenings • Participants were requested to engage in chemical dependency treatment for 12-16 weeks • Participants were encouraged to attend self-help meetings (e.g., Narcotics Anonymous) • Participants were advised not to drink alcohol, receive prescriptions for controlled substances, take

previously prescribed opioids, or use illicit drugs (no consequences for aberrant behavior listed) • Self-reported analgesia measured at initial visit and 6 months using 0-10-point NRS • Self-reported functioning measured on a 0-10-point NRS

Statistics • Fisher’s exact test was used to compare dichotomous variables • Two-tailed t-test or an ANOVA was used to compare continuous variables

Results

Participants

• 170 individuals screened, 130 were eligible and assessed o 1 patient never randomized, 1 declined to participate, and 74 were lost to follow-up

• 54 participants randomly assigned: n=26 to BUP/NLX and n=28 methadone • Treatment arms matched at baseline with exception of mean baseline functioning score , which was

greater for methadone arm compared to BUP/NLX arm (5.6 vs. 4.4, P=0.035) • Positive urine screens: 37% opiates, 13% cocaine, 37% for other drugs • Self-reported substance use in past 30 days: 38.9% opiates, 22.2% alcohol, 33.3% other drugs

Outcome

• 26/54 participants (48.1%) completed study, 13 in each study arm at 6 months o BUP/NLX: 11 stayed on medication, 2 crossed over to methadone o Methadone: 10 stayed on medication, 3 crossed over to BUP/NLX

• Participants who did not switch reported lower functioning than those who switched (P = 0.022) • Average daily dose of methadone 29.09 mg, average daily dose of BUP/NLX 14.93 mg/3.73 mg • No significant differences between treatment groups in percent change in pain from baseline; greater pain

reported at initial visit (M = 6.3, SD = 1.2) than at 6 months (M = 5.5, SD = 1.9) o 12.75% reduction in pain at medium effect size (Cohen’s d = 0.52)

• No significant differences found in percent change in functioning from baseline or treatment retention • Five BUP/NLX participants reported illicit opioid use at 6 months, vs. 0 in methadone group (P=0.039)

Author’s conclusion

Both BUP/NLX and methadone treatment for 6 months reduce chronic non-malignant pain in patients with co-existent opioid addiction. Limitations: • Small sample size • NRS used for pain and functioning may not be sensitive • Not double blind, no placebo-control group, high drop-out rate • Low reporting of opioid use at initial visit possibly due to question phrasing

Reviewer’s Critique Strengths Limitations

• Active comparator group • Divided daily dosing of medications • Patients self-reported functioning

• Strict exclusion criteria • Included few types of chronic pain • No psychiatric evaluation or formal opioid dependence diagnosis • Only 2 time points used to assess analgesia and functioning • Doses of BUP/NLX lower than typically used in patient population • No consequences or treatment modification for aberrant behavior

BUP/NLX was found to be as effective as methadone in reducing pain scores, with a statistically greater number of BUP/NLX participants reporting illicit opioid use. This suggests that BUP/NLX is comparable to methadone in treating pain but less efficacious in treating opioid dependence. However, the study’s high attrition rate and limitations reduce robustness and generalizability of the findings, underscoring the need for future investigations with a larger sample size.

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II. Pade, Cardon, Hoffman, & Geppert (2012)

Table 11. Prescription opioid abuse, chronic pain, and primary care: A Co-Occurring Disorders Clinic in the chronic disease model50

Objective Evaluate outcomes using BUP/NLX to treat veterans with co-occurring chronic non-cancer pain (CNCP) and opioid dependence in a primary care setting

Methods Design Retrospective chart review on veterans induced with BUP/NLX between June 2009 and November 2011

Sample

• Patients referred to the Co-occurring Disorders (COD) Clinic at Raymond G. Murphy VA Medical Center in Albuquerque, NM o Clinic established to manage patients with co-occurring chronic pain and substance abuse problems,

and high-dose or complex therapeutic pain management regimens

Intervention

• Assessments: physical exam, Brief Pain Inventory (BPI), Screener and Opioid Assessment for Patients with Pain (SOAPP), and Diagnosis, Intractability, Risk and Efficacy (DIRE)

• Induced with BUP/NLX then maintenance doses prescribed 3-4x daily, up to 28/7mg (range 6-28mg) Measurements & Monitoring • Patients received prescriptions monthly and were followed twice-monthly for first 2 months, monthly for

6 months, then every 1-3 months • Pain control and aberrant drug-taking behavior assessed at each visit; urine tox screens randomly taken • BUP/NLX discontinued and patients referred to more structured substance use disorder treatment

programs if patient returned to opioid use without provider consent, had ≥ 3 positive urine drug screens, missed ≥ 3 visits, had > 2 early refill requests, or experienced intolerable side effects or uncontrolled pain on doses up to 28mg

• Mean difference calculated from 5 pre-induction and 5 post-induction pain scores as rated by patients using analog scale (1-10) o If 5 pain scores not available, 0 used for pre-induction and 10 used for post-induction o Hypothesis: average pain scores would be higher while on BUP/NLX than prior to induction and

inadequate pain control would lead to BUP/NLX discontinuation

Statistics • Descriptive statistics collected • Two-tailed Student’s t-test used to determine statistical significance for differences in pain scores

Results

Participants

• 143 patients, 93% male, mean age 52 years (range 26-75 years) • Most common opioids: oxycodone (44%), methadone (16%), heroin (11%) • Mean daily morphine equivalent 184mg (median 120mg; range 30-375mg)

o Heroin not included in calculation due to variability in purity and unreliability of patient reports • Pain: 56% musculoskeletal, 39% mixed nociceptive and neuropathic pain

o 79 (55%) low back pain, 13 (9%) chronic headaches, 7 (4%) fibromyalgia

Outcomes

• Mean total daily dose BUP/NLX 16mg (range 6-28mg); most common regimens: o 8mg/2mg twice daily (26%), 8mg/2mg three times daily (19%), 4mg/1mg three times daily (18%)

• Pre-induction mean pain score 6.39 (95% CI 6.2 to 6.6) • Post-induction mean pain score 5.6 (95% CI 5.4 to 5.8, P < 0.001) • 93/143 (65%) patients continued treatment; 60/93 (65%) patients stayed on BUP/NLX for > 6 months • Of the remaining 50 who either discontinued treatment or were lost to follow-up:

o Six (12%) were released from clinic due to illicit drug screens o Eight (16%) discontinued due to ongoing pain o Seven (14%) remained off all opioids after discontinuation o Those who restarted opioid treatment were on lower doses of chronic opioids than before

Author’s conclusion

Chronic pain scores either stay the same or slightly decrease with BUP/NLX treatment may lead improved retention and fulfill the promise of BUP/NLX as an office-based treatment for opioid dependence. Limitations • Retrospective chart review with no comparator control group • Positive results cannot be conclusively attributed to BUP/NLX • No measures of patient functionality utilized

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Reviewer’s Critique

This retrospective chart review utilized repeated pain measures to assess efficacy of BUP/NLX maintenance therapy to target chronic pain and OUD. Although performed in a Veteran population, which may limit generalizability to non-Veteran patients, the high retention rate and statistically significant reduction in pain scores demonstrate that BUP/NLX can mitigate chronic pain while maintaining patient abstinence from opioid use.f

Strengths Limitations • Monitoring of pharmacy records, state prescription drug

monitoring, urine toxicology screens • BUP/NLX discontinued and patient referred out for

aberrant behavior • Conservative assumptions used for missing pain scores • Divided daily doses (BID, TID) appropriate for analgesia • Pre- and post-induction pain scores spanned wide range of

dates, mirroring real-world appointment schedules

• Single site and veteran population limit generalizability

• Unable to convert heroin into MMED • Did not report intake assessment findings (BPI,

SOAPP, DIRE) • Limited information on pain characteristics

III. Roux et al. (2013)

Table 12. Buprenorphine/naloxone as a promising therapeutic option for opioid abusing patients with chronic pain: Reduction of pain, opioid withdrawal symptoms, and abuse liability of oral oxycodone51

Objectives To assess effectiveness of buprenorphine in treating pain and reducing the abuse liability of oxycodone Methods

Design 7-week inpatient compensated research study with a repeated-measures design utilizing self-administration of oxycodone vs. money during laboratory sessions

Sample

• Participants recruited from New York City metropolitan area through print media advertisements completed an initial telephone interview for eligibility

• Lab screening included detailed medical history, drug use questionnaires, interviews with a psychologist and psychiatrist, medical evaluation by a physician, urine drug screens, McGill Pain Questionnaire (MPQ) used to assess clinical pain

• Prescription opioid use ascertained by: self-report, verification with prescribing physician, and/or presentation of prescription opioid bottles

Inclusion Exclusion • Under physician care for mild to

moderate chronic, non-malignant pain • Required to meet DSM-IV criteria for

opioid dependence • Not seeking treatment for opioid

dependence

• Current major Axis I psychopathology other than opioid dependence (i.e. schizophrenia or bipolar disorder)

• Met DSM-IV criteria for dependence on drugs other than opioids, nicotine, or caffeine

• Physiologically dependent on heroin or methadone • Primary diagnosis of neuropathic pain, malignant pain,

headache, or chronic lower back pain with failed surgeries • Current BUP maintenance or history of failed treatment

with BUP maintenance for pain

Intervention

• Participants admitted to New York Psychiatric Institute inpatient research unit for 7 weeks and transitioned from their baseline prescription opioid to BUP/NLX

Repeated measures design • Week 1: Participants stabilized on 1 of 3 doses

o 2/0.5mg, 8/2mg, or 16/4mg per day of BUP/NLX o Administered in equal divided doses (4 times daily) under double-blind conditions

• Week 2: laboratory testing performed while on same Week 1 dose • All participants received 3 doses of BUP/NLX in this 2-week interval fashion Laboratory Days During 2nd week, participants could self-administer oral oxycodone. Each lab day consisted of

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1. Sample session (~11:00am) – participants provided with random dose of oxycodone (either 0 = placebo, 10, 20, 40, or 60mg) and $20

a. Subjective, physiological, and analgesic effects measured after oxycodone dose administered 2. Choice session (~3:00pm) – participants could choose to self-administer the dose of oxycodone they

were given in that morning’s sample session, or receive money a. A self-administration task was required to receive 10% increments of oxycodone at a time, up to

100% of the morning oxycodone dose b. Same task was required to alternatively receive money in 10% increments up to $20 c. Self-administration task = an increasing number of finger presses on a computer mouse (50, 100, 200,

400, 800, 1200, 1600, 2000, 2400, 2800 presses) d. Immediately after task, money and/or amount of drug earned during the task was administered e. Opioid withdrawal symptoms and clinical pain measured 1 hour after 1st daily BUP/NLX dose

Assessments • Subjective Opioid Withdrawal Scale (SOWS; range 0-64) • 15-item Short-form MPQ (range 0-45)

Statistics

Pain • Bivariate analysis performed between MPQ score at baseline and MPQ score at various BUP/NLX doses

using a generalized estimating equations (GEE) model • Linear regression model based on GEE used to assess association between MPQ pain score and

BUP/NLX maintenance dose • Multivariate models used to identify factors associated with “oxycodone preference” using first MPQ

score and then SOWS score as explanatory variables Reinforcing Effects of Oxycodone • Repeated-measures ANOVA with significance level α = 0.05 • Mann-Whitney test used to compare difference between percent drug choice for placebo and each active

oxycodone dose Results

Participants

• 191 individuals assessed for eligibility, 140 excluded; 51 randomized, 31 completed the study, 6 of these were pilot patients so data was used for N=25 o Median age 48 (range 43-54), 36% women o 9 (36%) African American, 8 (32%) Hispanic, 8 (32%) Caucasian

• Median 60 MMED (range 38-144) from mainly oxycodone, hydrocodone, hydromorphone, tramadol • 9 (36%) had urine samples positive for cocaine at screening, 1 reported heroin use in past month

Outcome

• Median [IQR] MPQ score at screening was 38 [30-50] and 21 [15-31] under BUP/NLX maintenance • MPQ pain score significantly decreased between baseline and laboratory sessions

o Coefficient [95% CI] = −15.88 [−18.67,−13.10] (p<0.001) • Compared to 2mg/0.5mg BUP/NLX,

o 8/2mg BUP/NLX significantly decreased MPQ [OR(95%CI) = −1.68 (−3.15;−0.21); P=0.03] o 16/4mg BUP/NLX significantly decreased MPQ [OR (95%CI) = −2.74 (−4.21;−1.27); P<0.001]

• Oxycodone was not self-administered above placebo levels at any dose tested and did not vary as a function of BUP/NLX maintenance dose

Author’s conclusion

Among patients with co-occurring pain and opioid abuse, higher doses of buprenorphine are more effective than lower doses for simultaneously controlling both pain and opioid abuse.

BUP/NLX Dose

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Limitations • Inclusion/exclusion criteria reduce external validity • Highest dose tested 16mg • Population may choose other routes to abuse oxycodone • Laboratory conditions in inpatient setting

Reviewer’s Critique

This controlled study in a sample of patients with co-occurring pain and opioid dependence demonstrates that BUP/NLX can be used to reduce oxycodone self-administration while significantly reducing pain scores. However, the inpatient setting, participant compensation, methods of recruitment, and inclusion/exclusion criteria limit generalizability to a typical patient population outside of the study.

Strengths Limitations • Double-blind, randomized • Divided daily administration • Time point of 1 hour after BUP/NLX used for

analysis (absence of oxycodone effects) • Placebo dose of oxycodone used

• Recruitment methods • Compensated research study, potential max of $4410 • Excluded from analysis: self-reported heroin use and

positive methadone toxicology

Table 13. Comparison of Primary Literature Neumann et al. (2013) Pade et al. (2012) Roux et al. (2013)

Maximum dose of BUP/NLX 16/4mg 28/7mg 16/4mg Significantly reduced pain scores ü ü ü Effective in treating opioid dependence Less than methadone ü ~ Included prior heroin use ü ü Included mental health comorbidities ü Utilized divided daily dosing ü ü ü BUP/NLX discontinued if aberrant behavior ü Supportive therapy or counseling ü ü

CONCLUSION AND ADDITIONAL CONSIDERATIONS

1. Conclusion: Yes, BUP/NLX is effective in treating co-occurring pain and OUD. a. Studies investigating buprenorphine for treatment of CNCP demonstrate it is a safe and effective medication b. Studies investigating treatment of OUD/opioid dependence demonstrate that buprenorphine is effective in

maintaining abstinence from opioids c. Evidence for patients with co-occurring pain and OUD is limited and further investigations would benefit

treatment recommendations d. Although each study has its limitations, the investigations by Pade, Cardon, Hoffman, & Geppert. (2012),

Neumann et al. (2013), and Roux et al. (2013) demonstrate that buprenorphine/naloxone is effective in treating co-occurring pain and opioid dependence

2. Why is buprenorphine not more commonly used in this overlapping patient population? a. Complexity of diagnosis: uncomplicated addiction, physical dependence, uncontrolled pain, or all the above?

i. Treatments are generally centered on a singular diagnosis, and do not consider comorbidity/overlap b. FDA-approved use of BUP/NLX is for opioid dependence only

i. The 8 hours of training and application to SAMHSA for X-DEA waiver may be a barrier for practitioners ii. Health insurance coverage and employment restrictions may be a barrier for patients to seek treatment

iii. If health insurance companies don’t cover BUP/NLX: § Generic 8/2 mg SL tablet57: $8.12 - $10.42 (per each)

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APPENDIX

Abbreviations ACTH Adrenocorticotropic hormone NRS Numeric rating scale BUP Buprenorphine NSAID Nonsteroidal anti-inflammatory drug BUP/NLX Buprenorphine/naloxone OA Osteoarthritis CBT Cognitive Behavioral Therapy OIH Opioid-induced hyperalgesia CDC Centers for Disease Control ORL-1 Opioid receptor-like receptor 1 CHF Congestive Heart Failure OTP Opioid Treatment Program CLBP Chronic low back pain OUD Opioid Use Disorder CNCP Chronic non-cancer pain PTSD Post-traumatic stress disorder CNS Central nervous system SAMHSA Substance Abuse and Mental Health Services

Administration COPD Chronic obstructive pulmonary disease SL Sublingual CRF Corticotropin-releasing factor SUD Substance use disorder CRPS Complex Regional Pain Syndrome TBI Traumatic Brain Injury DOR Delta opioid receptor TD Transdermal DSM Diagnostic and Statistical Manual TENS Transcutaneous Nerve Stimulation GAD Generalized anxiety disorder VAS Visual analog scale HPA Hypothalamic-pituitary-adrenal VHA Veterans Healthcare Administration KOR Kappa opioid receptor VAS Visual analog scale LAI Long-acting injectable NRS Numeric rating scale MMED Milligram morphine equivalents per day NSAID Nonsteroidal anti-inflammatory drug MOR Mu opioid receptor OA Osteoarthritis