Pharmacotherapy for Chronic Pain Adapted from Penny Miller, BSc.(Pharm.), M.A. Change title slide

Goal: Provide the physician with practical information to support the medication management of patients with chronic pain as one part of the multimodal treatment to improve functioning, sleep and reduce pain. Learning Objectives: At the end of this session, the physician will demonstrate improved abilities to: Identify select medications that have evidence for the treatment of different types of chronic pain. Discuss when and how to use appropriate combinations of medications. Outline the importance for slow upward titrations and slow tapers off medications. Discuss the contraindications and controversies of medications used for chronic pain.

Medications cannot eliminate pain & are merely a part of the overall treatment Multimodal Therapeutic strategies for chronic pain and Associated disability

Adjuvants An adjuvant is a medication that is not primarily indicated for the treatment of pain, but which has some evidence for chronic pain management Tricyclic antidepressants SNRIs (selective serotonin reuptake inhibitors) Anticonvulsants Topical agents 24

Adjuvant Analgesics: Anticonvulsants/Neuromodulators For Chronic Neuropathic pain

Indication/ type and intensity of pain Choosing Analgesics The choice of a pharmacologic agent is based upon the following factors: Indication/ type and intensity of pain Efficacy of agent for the specific indication (NNT) Safety and experience of the agent (NNH) Renal and hepatic function of patient NNT= numbers needed to treat NNH= numbers needed to harm Co-morbidities (e.g. depression, cardiac disease) Drug interactions Cost Dosing Schedule Dosage forms ( oral, topical, parenteral, etc.) & strengths available

Summary of Evidence – Cochrane Summaries Drug Indication Clinical Considerations Gabapentin CD007938 2014 Postherpetic neuralgia NNT 8 Painful diabetic neuropathy NNT 5.9 1200 mg daily x 8-12 weeks Outcome: >50% pain intensity  Usually > 1 adverse effect Pregabalin CD007076 2009 Postherpetic neuralgia NNT 3.9 Fibromyalgia NNT 11 300, 450, 600 mg daily for benefits Likely moderate benefit but discontinue due to adverse effects Although the NNT does not appear to be very high and seems very favourable, keep in mind the outcome is >50% pain intensity reduction. This suggests there is likely some moderate benefit and may not necessarily be experienced by all patients. Consider using functional goals to evaluate and monitor therapy.

Summary of Evidence – Cochrane Summaries Drug Indication Clinical Considerations Carbamazepine CD005451 2014 No trial longer than 4 weeks for chronic neuropathic pain or fibromyalgia Not enough good quality studies to know the benefits & harms  likely should not be used Lamotrigine CD006044 2013 Neuropathic pain & fibromyalgia 200 – 400 mg daily appears to be effective but low quality evidence, unable to quantify; likely 10% will have skin rash

What is the limitation of the evidence? Gabapentin Issues of 40% of trials were unpublished Pregabalin Issue of unpublished trials Carbamazepine no trial beyond 4 weeks Likely should not be recommended Lamotrigine 200 – 400 mg daily- There is no convincing evidence this is effective in treating acute or chronic pain Painful Diabetic neuropathy (PDN); IMMPACT definition of pain applied for moderate and substantial benefit in Gabapentin trials http://www.acfp.ca/Portals/0/docs/TFP/20120402_011933.pdf

Adjuvant Analgesics/ Co-analgesics Anticonvulsants/Neuromodulators: Gabapentin Dose: start at 100 mg at bedtime and increase slowly (every 3 days) to 1800 – 3600 mg daily as tolerated (divided as three times daily) Adjust dose in renal impairment (clearance is decreased) Absorption is inversely dependent on dosage: Gabapentin oral bioavailability: 80% with100 mg tid 27% with 1600 mg tid Analgesic effect seen at 2 to 3 weeks of therapeutic dose is a branched- chain amino acid (similar to leucine) which affects oral bioavailability Clin Pharmacokinet 2010;49(10):661-669

Adjuvant Analgesics/ Co-analgesics Anticonvulsants/Neuromodulators: Pregabalin Analgesic effect is seen within first week of therapeutic dose Dose: start with 25 mg qhs and increase slowly (every 3 to 7 days) as tolerated to 150 mg daily or 150 mg bid (Max 600 mg daily) For all anticonvulsants, taper to elimination to avoid seizures even with no history of convulsive disorder. Pain Res Manage 2007:12(1):13-21 Guidelines CPS; Pain Res Manage 2006;11(1):11-38 Chronic Pain review – Lynch Lyrica 300 mg starting dose caused significant analgesia within one to 3 days.

Adverse Effects Gabapentin Pregabalin Somnolence 21.4% 29.2% Dizziness/ ataxia 28% 22.2% Dry mouth 4.8% 9.1% Peripheral Edema 8.3% 6.1% Blurred Vision 5.9% 6.4% ↓ Concentration/attention 2.7% 5.4% Clin Pharmacokinet 2010;49(10):661-669 Anesth Analg 2007:105:1805-15 Sedation is #1 reason to DC (4%) For Gabapentin: Cochrane Review: Cochrane Database Syst Rev. 2011 Mar 16;3:CD007938. 66% have at least one adverse event; 12% withdrawal because of an adverse event; 4% serious adverse events which were no more common than with placebo.

Anticonvulsant- Risk of suicidal thoughts and behaviour 0.43% on Anticonvulsants versus 0.22% on placebo Evident as early as 1 week after starting treatment Risk is highest in Epileptic cases Neurology 2010; 75: 335-340 New Engl J Med 2010; 363: 542-451 CNS Drugs. 2009;23(4):281-92. (FDA 2008) Meta- analysis of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs (antiepileptic drugs) showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behaviour compared to patients randomized to placebo. Andersohn F, Schade R, Willich SN. et al .Use of antiepileptic drugs in epilepsy and the risk of self-harm or suicidal behaviour. Neurology 2010; 75: 335-340 5 Arana A, Wentworth CE, Ayuso-Mateos JL. Arellano FM. Suicide-related events in patients treated with antiepileptic drugs. New Engl J Med 2010; 363: 542-451 CNS Drugs. 2009;23(4):281-92. Suicidality in people taking antiepileptic drugs: What is the evidence?

Adjuvant Analgesics: Antidepressants For chronic pain

Summary of EvidenceCD005454 2007; CD008242 2012 Drug Indication Clinical Considerations Amitriptyline Painful diabetic neuropathy/post-stroke pain with fibromyalgia/postherpetic neuralgia NNT 4.6 Potentially biased data – only 38% benefited from therapy Median duration 6 weeks 64% of participants with ≥ 1 adverse effect A/E leading to withdrawal: NNH 28 Minor A/E: NNH 6 venlafaxine Moderate pain relief NNT 3.1 A/E leading to withdrawal: NNH 16.2 Minor A/E: NNH 9.6 Antidepressants: TCAs or venlafaxine Diabetic neuropathy NNT 1.3 Postherpetic neuralgia NNT 2.7 Duloxetine CD007115 2014 Diabetic peripheral neuropathy NNT 5 Fibromyalgia NNT 8 Studies were over 12 weeks – ie short duration 60 mg daily ~12.6% participants dropped out due to A/E Third row refers to any evidence for TCAs or venlafaxine

Antidepressants/ TCAs Adverse effects: Anticholinergic side effects (dry mouth: 30% amitriptyline/10% nortriptyline), constipation, urinary retention, blurred vision, tachycardia, cognitive impairment) Sedation (30% amitrip/2% nortrip), postural hypotension Cardiac arrhythmias ( especially in overdose) Weight gain Precautions: Benign prostatic hypertrophy, closed angle glaucoma, CV disease Screening EKG for cardiac conduction abnormalities if > 40 yo Risk of suicide by overdose (> 750 mg or 15 - 20 mg per kg) Dose: start with 10 mg amitriptyline at bedtime and titrate slowly ( analgesic response typically seen with 10 – 75 mg daily) Amit Nortrip dry mouth 30% 10% sedation 30% 2% The most important ECG feature of toxicity is prolongation of the QRS interval, which indicates a high risk of ventricular tachycardia. In very severe poisoning the ECG may be bizarre. Rarely, prolongation of the PR interval or heart block may occur. QT interval prolongation and torsade de pointes has also been reported.

Antidepressant (TCA) Monitoring Efficacy for improved sleep (immediate) Efficacy for improved pain control (1 -2 weeks) Raskin et al Pain Med 2005 Efficacy for improved mood (6 – 8 weeks) EKG baseline prior to initiation in patients over 40 years old Must taper off to avoid antidepressant discontinuation syndrome Antidepressant discontinuation syndrome: (FINISH) Flu-like symptoms, insomnia, Nausea, sensory disturbances (electric shocks), Hyperarousal ( anxiety, confusion, hypomania)

Drug Interactions with TCAs TCA + Codeine – TCA block hepatic cytochrome 2D6 isoenzyme so inhibit conversion of codeine to morphine (also, tramadol conversion to active metabolite) TCA +CNS depressants (alcohol, opioids)->sedation TCA + other anticholinergic – paralytic ileus TCA + SSRI or SNRI + Triptan = serotonin syndrome TCA + SSRI or SNRI + tramadol = serotonin syndrome Celecoxib also : Journal citation: Proceedings of the National Academy of Sciences, advance publication online Dec. 1, http://www.pnas.org/cgi/doi/10.1073/pnas.0909765106

Adjuvant analgesics/ Co-analgesics Antidepressants - serotonin-norepinephrine reuptake inhibitors (SNRI) Mechanism of action: increase levels of norepinephrine ( and serotonin) to stimulate the descending pain pathway Duloxetine (Cymbalta ®) Start at 15 mg once daily (mix 30 mg capsule with apple sauce) and titrate slowly up to 60 mg daily Dosage adjustment not necessary in renal dysfunction; caution with hepatic insufficiency Venlafaxine (Effexor ®) Start at 37.5 mg once daily and titrate slowly up to 150 mg (225 mg) daily Adverse effects: nausea, headaches, stimulation/sedation, sweating, increased blood pressure Minimal anticholinergic side effects Pain Res Manage 2007:12(1):13-21 Guidelines CPS; Pain Res Manage 2006;11(1):11-38 Chronic Pain review – Lynch

Combination Therapy – Neuropathic Pain CD008943 2012 Lots of different combinations difficult to evaluate & recommend one particular combination One sufficient evidence for gabapentin + opioid vs. gabapentin alone N = 386, 2 studies Modest benefits, but combination was better A lot more adverse effects Tends to have overlapping adverse effects of CNS sedation High dropout rates in studies – limit utility of such combinations

Topical agents

What is the evidence for topical agents? Capsaicin low dose 0.075% gel: Systematic review with usage over 6 to 8 weeks NNT 6.6 (95% CI 4.1-1.7) for NP Cochrane Database Syst Rev 2012;9:CD010111 NNT 8.1 for osteoarthritis (pain reduction of 33-55% vs 20 -27% placebo) Rheumatology (Oxford) 2011;50(5):911-20 “it unlikely that low-concentration topical capsaicin has any meaningful use in clinical practice” Cochrane Database syst. Rev. 2012 Sep 12;9:CD010111 NSAIDs : Meta-analysis of RCTs (diclofenac) NNT 4.6 (95% CI 3.8 -5.9) for knee osteoarthritis BMC Musculoskelet Disord 2004:5:28; J Rheumatol 2006;33(9):1841-4 Contact dermatitis risk

Treatment Principles First consider non-drug measures. Is a medication ESSENTIAL? (i.e. clear diagnosis) Is the treatment GOAL/ outcome clear? Initiate one drug at a time. Keep it simple. Select pharmacologic classes with efficacy demonstrated (ideally) in multiple RCTs Be aware that response will vary between patients Start with very low doses and titrate slowly

Treatment Principles… When introducing a new treatment, consider overlap with old treatments to avoid deterioration in pain control. If the new medication is well tolerated, then continue to titrate to effective or acceptable pain relief (30% to 50% reduction) Consider adding a second agent with a different mechanism of action if the first agent is providing partial relief yet pain remains ≥ 4/10 If the medication is ineffective, then slowly taper off the medication

Treatment Principles… Consider side effects, drug interactions, cost and abuse potential Be aware of comorbidities such as depression, anxiety and insomnia Design a future plan to slowly taper off most medications for chronic pain Educate patients about their medications Regularly update the medication lists of patients (OTC, herbal, Rx)

Summary The complex task of pain management should be approached with a logical foundation: A detailed history and physical Any appropriate testing that can facilitate diagnosis and treatment Establishment of realistic and desired common goals of further treatment and/or evaluation Formulation of a treatment plan that may include only a rational, evidence-based approach in the use and selection of medications Flexibility in modification of treatment based on periodic re- assessment Referral to a pain specialist when appropriate A trusting and caring relationship is an important imperative