Dr. Joel Bordman November, 2013

Dr. Joel Bordman November, 2013 1

Faculty: Dr. Joel Bordman Relationship with commercial interest: has been on an advisory board or a speaker for the following companies in the last 24 months: Janssen-Ortho Purdue Pharma Paladin Labs Reckitt Benckiser Lilly

No commercial support

In developing this program, I have ensured that all recommendations with respect to products made by the companies in Slide 1 are based on published evidence.

To review the treatment of ACUTE pain in the opioid dependent patient To review the treatment of CHRONIC pain in the opioid dependent patient To compare MMT with methadone for pain treatment To review buprenorphine effectiveness in the treatment of pain

Physical / Rehabilitative Psychological Medical Pharmacological Interventional 6

ACUTE pain treatment in MMTP Opioid Non-opioid CHRONIC pain treatment in MMTP Opioid Non opioid

An acute pain condition is NOT the time to punish someone for opioid dependence Avoid opioid of past misuse Tie in dispensing to methadone dispensing Communicate with other HCPs, know the usual natural history of pain condition Possible tramadol, tapentadol

Recommended 3 rd -line treatment for moderate to severe pain 1 Starting dose: 2,3 37.5-75 mg every 4-6 hours (short-acting) 100-150 mg/day (controlled-release) Usual maintenance dose: 2,3 37.5-75 mg every 4-6 hours to a maximum of 300 mg/day (short-acting) 100-150 mg/day to a maximum of 300-400 mg/day (controlled-release) Less constipation and nausea than other weak opioids (e.g., codeine), but is more expensive 1 Contraindicated in patients taking MAOIs* 2,3 *Please refer to product monograph for full product and prescribing information. 1. Moulin DE, et al. Pain Res Manage. 2007;12(1):13-21. 2. TRAMACET (tramadol hydrochloride/acetaminophen) Product Monograph. 2008. 3. ZYTRAM XL (tramadol hydrochloride) Product Monograph. 2008.

3 signs or symptoms from the following triad: Cognitive and/or behavioral changes Confusion, lethargy, agitation, coma Autonomic instability Hyperthermia (fever), diarrhea, mydriasis, tachycardia, nausea/vomiting, diaphoresis Neuromuscular changes Myoclonia, tremor, seizure, hyperreflexia, clonus, muscle rigidity, ataxia Masson et al. Medicine. 2000;79(4);201-9.

Mechanisms of Action Synergistic activity of two mechanisms of action: µ-opioid receptor agonist 50 times lower affinity for the µ-opioid receptor than morphine (animal models) But only 2 3 times less potent than morphine with respect to analgesic effect (animal models) Inhibition of norepinephrine reuptake The synergistic effect is observed in experimental models of nociceptive and neuropathic pain Schröder W, et al. J Pharmacol Exp Ther 2011 Jan 24. Epub ahead of print Bee LA, et al. Pain 2011;152:131 NUCYNTA * CR Product Monograph. Janssen Inc., 2010 *All trademark rights used under license

NSAIDS, COX II Inhibitors Acetaminophen

Acute: dose maximum 4g/day (or 3.2g/day or 2.6g/day) Hepatic metabolism hepatotoxicity Alcohol Toxicity with chronic users Fasting/malnutrition No indication for treating inflammatory condition

RCT Evidence in acute nociceptive, post-op, inflammatory arthritis & dental pain Useful for mild-moderate nociceptive pain and inflammatory pain

Inflammatory pain, opioid sparing Adverse effects GI (4-16%) CV (thrombosis, MI, CVA) Renal Caution Bleeding risk Renal impairment Long term use Drug interactions (caution with ASA for CV risks)

No effect on platelets (good for post-op pain) (NOT post CABG surgery) (Stephens JM. Pharmacotherapy, 2004) ½ risk of complicated PUD (2%/yr) (VIGOR) Concurrent ASA reduces the GI protective effect (CLASS) Increased risk of CV events (MI & CVA) Celocoxib may be different

ACUTE pain treatment in MMTP Opioid Non-opioid CHRONIC pain treatment in MMTP Opioid Non opioid

http://nationalpaincentre.mcmaster.ca/opioid/ CMAJ June 15, 2010 18

As a general rule adding another long term opioid should be avoided (especially the past opioid of choice) Methadone as a split dose considered Very important to have well thought out goals and an exit strategy Can switch to methadone for pain if your diagnosis was incorrect (MD needs pain exemption)

Adapted from Cleeland CS, Ryan KM, 1994

µ and delta opioid receptor agonist Analgesia and typical opioid SE profile; may have more diaphoresis and flushing NMDA receptor antagonist May help to prevent or reverse opioid tolerance and hyperalgesia Theoretical advantage for neuropathic pain Inhibits re-uptake of norepinephrine & serotonin Evolving evidence for this mechanism-based analgesia via descending modulation in neuropathic pain Lynch ME. Pain Res Manag 2005; 10(3):133-44. Davis MP.Support Cancer Care 2001; 9;773-83. Fishman SM.Pain Med 2002; 3:339-48.

Methadone was disproportionately involved in a third of opioid-related deaths nationwide during the 2000s, although representing less than 5% of total opioid prescriptions. Webster, 2011 pain topics.org 22

Advantages High oral bioavailability Lack of significant active/toxic metabolites No accumulation in renal insufficiency effective in hemodialysis patients Dosing change not necessary in hepatic failure Non-opioid pharmacology (NMDA antagonist activity, reuptake of serotonin/norepinephrine inhibitor) Neuropathic pain, opioid-induced tolerance/ hyperalgesia Liquid form allows for easy adjustment of dose Good for individuals with swallowing difficulties Source: Peng 2005

Disadvantages Long and unpredictable half life Potential for accumulation and overdose during titration Unpredictable equianalgesic potency compared to other opioids Variable protein binding Social stigma because of it s association with addiction treatment Parenteral formulation not easily accessed Subcutaneous route associated with localized adverse reactions High doses and IV formulation carries potential risk of QTc interval prolongation and Torsades de pointes Drug interactions Source: Peng 2005

Non opioids Acetaminophen NSAIDS COX-2 Inhibitors Adjuncts Antidepressants Anti epileptics Topical agents

TCA Gabapentin or pregabalin SNRI Topical lidocaine* Tramadol or Controlled-release opioid analgesic Add additional agents sequentially if partial but inadequate pain relief Fourth-line agents TCA: Tricylic antidepressant; SNRI: Serotoninnorepinephrine reuptake inhibitor *5% gel or cream; useful for focal neuropathy such as postherpetic neuralgia. Cannabinoids, methadone, lamotrigine, topiramate, valproic acid. Do not add SNRIs to TCAs. Moulin DE, et al. Pain Res Manage. 2007;12(1):13-21.

NNT NNH Tricyclics 2.1-2.8 15.9 Opioids 2.1-5.1 17.1 Gabapentin 4.3-6.4 32.5 Pregabalin 3.8-5.6 10.6 Tramadol 4.8-4.9 13.3 Venlafaxine / Duloxetine 5.0 13.1 (NNT= # of patients treated to get 1 with a 50% pain reduction) (NNH = # patients treated for 1 to drop out of the study) Finnerup N.B. et al. Pain 2010; 150: 573-581

This has become a part of modern pain management May experience only a partial response to monotherapy Cannot tolerate adverse events at analgesic doses of one agent May have positive synergistic effects of combined agents from different medication classes Consider the following when selecting combined regiments: Side effects Medication interactions Ease of use Cost McCarberg b, J Fam Pract, 2004;53 Fishbayn DA, Am J Phys Med Rehab 2005;84

Peripheral Sensitization Descending Inhibitory Pathways (NE/5HT, enkephalins) Na+ Carbamazepine Oxcarbazepine Tricyclic antidepressants Topiramate Lamotrigine Lidocaine Spinal Cord Tricyclic antidepressants Serotonin-norepinephrine reuptake inhibitors Selective serotonin reuptake inhibitors Alpha adrenergic blocking agents Opioids Tramadol Cannabinoids Central Sensitization Ca++ Gabapentin Levetiracetam Oxcarbazepine Lamotrigine Pregabalin NMDA Ketamine Dextromethorphan Methadone Memantine Adapted from Beydoun, et al. J Pain Symptom Manage. 2003;25(suppl 5):S18-30.

Mechanism: Reduction in action potential firing of sodium channel activity Inhibition of reuptake of norepinephrine and serotonin Common adverse events Dry mouth, constipation, daytime drowsiness, urinary retention, orthostatic hypotension, arrythmias, weight gain Caution: CVD Urinary retention Glaucoma Risk of OD

Robust evidence of efficacy 1 Inexpensive medications 1 Nortriptyline* is are better tolerated than amitriptyline* 1 Starting dose and titration: 10-25 mg/day, at bedtime or in divided doses every 12 h; increase dose weekly by 10-25 mg/day 1,2 Usual maintenance dose: 50-150 mg/day 1 *Please refer to product monograph for full product and prescribing information. 1. Moulin DE, et al. Pain Res Manage. 2007;12(1):13-21. 2. Gilron I, et al. CMAJ. 2006;175(3):265-75.

Blocks a2d receptor of N-Type Ca channels Neuropathic pain, migraine, mood stabilizer,, No known adverse drug interactions Synergistic effect with opioids (Gilron, 2005) 100mg hs test dose then titrate by 300mg q3 days up to 3600mg+ (tid dosing) Adjust dosing in renal insufficiency

Action same as GPN Officially indicated for neuropathic pain (PHN, DN, Central NeP), fibromyalgia Linear absorption kinetics BID dosing Side effects similar to GPN Start 25-75mg qhs then bid x7; 150mg bid x7 300 bid x 7 Effects seen within 1 week of adequate dosing Adjust dosing in renal insufficiency

Most common events which occurred in 5% of pregabalin patients and statistically significantly more frequent and greater than placebo. 1. Lyrica Product Monograph. Pfizer Canada Inc. Last revised: June 21, 2010.

Independent analgesic effect (significant pain relief) has been demonstrated within the first week Starting dose: 60 mg/day 3 (A starting dose of 30 mg may be considered for tolerability reasons, with a target dose of 60 mg/day within 1-2 weeks 1 ) Usual maintenance dose: 60-120 mg/day (maximum 120 mg/day) 2,3

Duloxetine 120 mg/d (n=147) Direct Analgesic Effect 79% of total treatment effect (p=0.045) through direct analgesia Indirect Treatment Effect 21% of total treatment effect (p=ns) through improvement in depressive symptoms Results for the 60 mg/day group are not presented. 1. Russell IJ. Pain 2008;136(3):432-44. Improvement in Pain 52.1% reduction in average pain severity at 3 months (p=0.008)* * The 52.1 % improvement in pain is a post hoc analysis showing greater than or equal to 30% reduction in pain

Most common events which occurred in 5% of duloxetine patients and statistically significantly more frequent than placebo. * Pooled data from all patients receiving duloxetine 60 mg/day, 120 mg/day and 60 mg/twice per day in randomized placebo controlled clinical trials 1. Cymbalta Product Monograph. Eli Lilly Canada Inc. Last revised: October 6, 2010.

Nabilone (Cesamet) 0.5, 1.0mg BID cancer chemo nausea and vomiting THC / CBD spray (Sativex) MS neuropathic pain severe cancer pain on opioids

Human evidence is very limited thus far 4 published RCTs smoked cannabis (Abrams 2007; Ware 2010) Smoking is a dirty way to give a drug In palliative care may not be a concern 1 published RCT on nabilone in FM pain (Skrabec, 2007) There may be a dose window for pain (Wallace, 2007) Adverse effects: CNS depression, psychosis, ataxia, disorientation, addiction, effects on memory and motor function, decreased IQ, gateway drug Abrams et al. Neurology 2007; 68(7): 515-21 Aldington et al Thyorax 2007; 62(12):1058-63 Broadbent et al. JAMA 2008; 299(5):535-31 Wallace et al. Anesthesiology 2007; 107(5):785-96 Ware et al. CMAJ 2010; 182(14):694-701

Poison is in everything, and no thing is without poison. The dosage makes it either a poison or a remedy. (Paracelsus 1493-1541) 40

Multiple mechanisms of action Migraine, mood stabilizer, (diabetic neuropathy) Main S/E cognitive impairment (occurs early) Other S/E: renal stones, metabolic acidosis, depression Start at 25mg hs x 1wk then titrate Oral hypoglycemic drug weight loss Positive studies in decreased alcohol consumption

Lidocaine (USA) Capsaicin cream Diclofenac diethylamine gel 1.16% 42

According to a comprehensive review of the clinical research evidence, helping certain patients overcome chronic musculoskeletal pain and fatigue syndromes may be as simple, well tolerated, and inexpensive as a daily supplement of vitamin D. Leavitt, 2008. Pain topics.org 43

Endocrine conditions Hypothyroidism, Hyperparathyroidism Inflammatory conditions Early stages of inflammatory arthritis (when joint swelling is minimal) Polymyalgia rheumatica (older patients) SLE, Seronegative spondyloarthropathies Hwang E, Barkhuizen A. Update on rheumatologic mimics of fibromyalgia. Curr Pain Headache Rep. 2006 Oct;10(5):327-32. Review.

Neurological conditions Multiple sclerosis, Peripheral neuropathy Drug-related causes Statin induced body pain Aromatase inhibitor body pain Chemotherapy-related neuropathy

CBC, ESR, Uric Acid CRP, ANA, RF TSH Serum Calcium and phosphate CK

Sublingual burprenorphine is effective in the treatment of chronic pain syndrome Herbert L. Malinoff, et al American Journal of Theraputics 12, 379-384 (2005)

95 patients referred from local pain clinics failed treatment Increased pain level Worse functional capacity Opioid addiction (8%) Rotated to sublingual Buprenorphine 4-16mg in divided doses

86% reported moderate to substantial pain relief with improved mood and functioning 6 discontinued due to side effects or increased pain

www.pain-topics.org 50

To review the treatment of ACUTE pain in the opioid dependent patient To review the treatment of CHRONIC pain in the opioid dependent patient To compare MMT with methadone for pain treatment To review buprenorphine effectiveness in the treatment of pain

Physical / Rehabilitative Psychological Medical Pharmacological Interventional 52