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Home , Essential tremor, Restless legs syndrome, Topiramate, Tremor

© www.RxFiles.ca - Jan 2010 RxFiles: Q&A Summary Brent Jensen BSP, Loren Regier BSP BA

Essential (ET) - Treatment Options

What are some general characteristics of “”? 1,2,3,4,5 >5% ƒ Most common adult tremor (in elderly ); autosomal dominant inheritance; offspring may have 50% chance of getting ƒ Affecting about 500,000 Canadians; starting at any age (Mean age 45yr; bimodal: 20s & 60s); equally men & women ƒ Slowly progressive; esp. amplitude worsens over time; no bradykinesia, rigidity or postural instability. However, in cases with longstanding or severe ET, resting tremor may be seen (but without the other parkinsonian features). ƒ Often benign but can cause functional (occupation, activities, writing, drinking & eating) & social impairment ƒ Tremor: postural & kinetic, usually bilateral, symmetric & rhythmic; in forehands & hands ~95% (dominant often first; eventually both hands); head ~34% tremor & voice ~12% shakiness may occur; occasionally trunk, legs, jaw & lip tremor

What causes essential tremor? ƒ Primary – Idiopathic/Essential: most common (>60% will have a positive family history); ??environmental ƒ Rule out: metabolic disturbances, drug eg. benzo or withdrawal, drugs, , & ƒ : Enhanced physiological tremor, Dystonic, Task-specific, Parkinsonian, Holmes (rubral tremor rare), & Wilson's disease (consider if <40yr without family history of tremor, esp. if , & psychiatric features; abnormalities & Kayser-Fleischer corneal rings). ƒ Drugs which exacerbate physiologic tremor: , , , beta agonists eg. , , calcitonin, , cyclosporin, , ephedrine, lead, Li++, , , SSRIs, steroids, , thyroid hormones, TCAs & .

What non-pharmacological therapies can be recommended? ƒ Tremor is often the sole symptom but may be worsened by , , cold & social interaction. Alcohol, which may relieve the tremor, must be used appropriately. Adequate REST is important. Adding wrist weights to a limb may

reduce amplitude of the tremor. Relaxation techniques such as meditation, yoga, hypnosis and biofeedback may help.

When should drug treatment be considered for ET? ƒ Consider “no drug treatment” or “treatment only for specific events” (e.g. party, special events) if not severe. ƒ If disabling only during periods of stress & consider "PRN" use of or ƒ Consider regular drug therapy if ET significantly impacts daily activity or psychologic distress.Meds don't cure or slow progression

What are the primary drug treatments options for treating ET? ƒ Beta-blockers & alone or in combination are the mainstays of therapy (>50% of the pts have symptomatic benefit). Dosages may have to be increased with time. , , & botulinum injections may be useful in select cases. Surgical intervention, if tremors are refractory to medical management, may be indicated. { (DBS) to Vim nucleus of the has similar efficacy to of the Vim to improve contralateral limb tremor, but DBS has fewer serious SE.}

Table 1: Drug Regimen Options in ET 1,6,7,8 Class Drug (g=generic avail.) Dose (po) in ET $/month Comments INDERAL,g ~$10 CI: asthma, uncompensated heart failure, Beta-blockers Propranolol 10-20mg po bid initially st FDA approved (best studied); ~ 50% respond to tx ↓ heart rate (<50),↓BP (<90mmHg) Ö1 line in moderate to 40-80mg po bid-tid $10-15 severe limb ET; may be Both regular & LA effective; SE: wheezing, , , Some OK on 10-40mg prn prior to stressful situations 120-160mg LA po od ~$40-45 drowsiness & ; ↓HR/BP helpful for head tremor; More data/effective long term than other β-blockers Range: 120-240-320mg/d but review CI) Non-selective β-blocker (vs metoprolol - β1-selective) ↓ amplitude not frequency of tremors

{Also 80-160mg/d; non-selective & antiarrhythmic} Metoprolol LOPRESSOR,g 50-100mg bid;100mg SR od ~$15 9 Anticonvulsants MYSOLINE,g 62.5mg hs (↑62.5mg q7d) $10 SE: dizziness/, /unstable gait, st drowsiness, headache, polyuria & ÖPrimidone is 1 line in ~ 50% respond to tx 125-250mg po bid - tid $15 moderate to severe limb ~ similar efficacy to propranolol in trials Combination propranolol & primidone ~ one study found 250mg/d = 750mg/d (efficacy)10 Range: ≤250-1000mg/d occasionally useful.

ET; especially those ~ potential of 1st dose SE reaction, ∴ start low dose!

intolerant to 11,Ondo 06 SE: dizziness, unstable gait, drowsiness, β- blockers (Primidone Topiramate TOPAMAX,g 100-200mg bid $100-150

(Start: 25mg daily; ↑ by 25-50mg/wk to ↓ SE) ↓weight, , & more effective than Effective in trials but high (40%) drop-out rates / poor tolerance ) difficulty word finding

Gabapentin NEURONTIN,g 400-600mg tid $66-115 SE: , dizziness, fatigue, euphoria, ÖOthers 2nd line Trial efficacy inconsistent (Start: 100-200mg to ↓SE) drowsiness & ↓ libido; abuse potential

{  ⊗ LYRICA 75-300mg bid more studies needed} $330-490 SE: dizziness, flu symptoms, , euphoria Benzodiazepines 12 Clonazepam RIVOTRIL,g 0.25-0.5mg tid ~$16 Limited benefit on tremor, but has ÖIntermittent use for Options Line Limited trial data; up to 6 mg/day but ↑ sedation hypnotic effect & may help ↓ anxiety.

nd

2 stressful situations making XANAX,g 0.25-0.5mg tid ~$16 SE: tolerance, falls, dependence, daytime

tremor worse Limited trial data sedation & abuse / potential Botulinum Botulinum BOTOX Head: 50-100units Max 400 ~$4 per SE: Hand tremor: muscle & Toxin A13 Voice: 0.6-15units UNIT paresthesia. SE: Voice tremor: breathiness, Repeated every ~3months hoarseness & swallowing difficulties. (BTX) Option: disabling head or voice tremor BP=blood pressure CI=contraindication ET=Essential Tremor Li= Pts=patients SE=side effects Other Possible Options: 100mg bid $30; 50-100mg od ~$20; 0.1mg tid $25; 12.5-75mg/d ~$100 (but sedation, agranulocytosis, etc.) ; 5-10mg hs $26-45; 14 500-1000mg bid $100-200; methazolamide 12.5-25-50mg tid ~$25-60; phenobarbital 30-60mg bid~$15; & sotalol 40-80mg po bid~$25-40. Deep Brain Stimulation (DBS) surgical option. NOT recommended: , isoniazid, & trazodone. ET Websites: www.essentialtremor.org Drug treatment by ET type: Limb/Hand: propranolol, primidone, anticonvulsants, benzodiazepines; Head: propranolol, BTX; Voice: BTX Specific drug charts at www.RxFiles.ca

See next page for: (RLS) Treatment Options . © www.RxFiles.ca - Jan 2010 RxFiles: Q&A Summary Loren Regier BSP BA, Brent Jensen BSP

Restless Legs Syndrome (RLS) - Treatment Options

What are the diagnostic criteria for “restless legs”? 15,16,17 {Also known as: Ekbom's syndrome} ƒ Distressing desire to move legs or other body parts; often accompanied by uncomfortable sensations (e.g. creeping) ƒ Symptoms brought on by, or worsen with rest (sitting or lying down). Overall prevalence is ~10% in general population. ƒ Urge and sensation is relieved with movement or reduced temporarily (e.g. walking, stretching) ƒ Symptoms worsen in evening or at night (often worst between midnight-4am; thus causing major disruption of ) ƒ Optional: involuntary limb movements while awake; periodic limb movements while sleep (as per patient or partner)

What causes restless legs? ƒ Primary – Idiopathic: most common (~ 50% will have a positive family history) ~5% ++ + ++ ƒ Secondary, non-drug: , , , serum , ; ↓Mg , K , Ca ++ ƒ Drug causes: , antinauseants, antipsychotics, dopamine antagonists, Li , metoclopamide, SSRIs & TCAs, CCBs. Other: Discontinuation of may precipitate RLS. Caffeine containing products.

18,19 What non-pharmacological therapies can be recommended? (Note: non-drug therapies not well studied) ƒ Avoiding caffeine/chocolate, alcohol, ; keeping a regular sleep routine, rubbing limbs, walking / exercise (combination resistance and aerobic) , stretching; doing mentally alerting activities, warm or cool baths. ƒ Pneumatic compression devices effective: worn for 1hr upon symptom onset. inflated to 40cm H2O air pressure for 5 seconds during every minute

When should drug treatment be considered for restless legs? ƒ Consider “no drug treatment” or “treatment only for specific events” (e.g. air travel, theatre) if not severe. ƒ Treat “intermittently” for intermittent symptoms. Levodopa’s fast onset makes it suitable for intermittent use. ƒ Consider regular drug treatment if RLS significantly impacts daily activities or disturbs sleep.

What are the primary drug treatments options for treating RLS? ƒ Dopaminergic therapy is often the current drug treatment of choice. “Rebound” and “Augmentation” can arise with dopaminergic agents, especially levodopa (LD). Rare: ↑gambling behavior {Other drugs have also been studied; see Table 1.} ƒ Rebound: worsening of symptoms when LD levels fall, usually during night or early day Management Options: 1) Repeat dose; 2) Add Levodopa CR to IR ƒ Augmentation: appearance of more severe RLS symptoms earlier in day, before dose. Management Options: 1) If on LD, switch to

Table 1: Drug Regimen Options in RLS 20,21,22,23,24,25,26 Class Drug (g=generic avail.) Dose (po) in RLS* $/month Comments 1-3hrs pre hs Dopamine Agonists MIRAPEX,g 0.125-1.5mg hs $50 Canadian & FDA approved, Effective; t½ =8-12hrs (1st line in moderate to (generic avail., but not officially indicated for RLS) 0.5mg/d Typical dose ≤0.5mg/day; scored tabs 1-3hrs pre hs severe RLS; Gradually REQUIP,g 0.25-4mg hs $30 FDA approved; RCT evidence, Level A; 12wks ↑dose q2-3days) 2mg/d Typical dose =2mg/day; t½ =6hrs NNT=~6; NNH=77 to D/C tx Non-ergot dopamine agonists more effective than placebo at ↑QOL & sleep; however strong placebo effect & ↑ SEs (, dizzy, SE: nausea, dizziness, , fatigue. Efficacy maintained for 1yr; minimal augmentation. PERMAX, no longer available USA Mar’07 & CDN Aug’07 fatigue, somnolence … 26 $17 (≤400/100 mg); fast onset ~20min if ac; Levodopa (LD) , LD/ PROLOPA 50/12.5mg hs Dopamine Precursor LD/Carbidopa SINEMET,g ½-1, 100/25 mg tab hs $15 useful for intermittent prn treatment st (1 line for prn dosing in SINEMET CR,g (may give regular & CR tabs together Rebound & Augmentation common if $45 ≥200mg & requires discontinuation mild to moderate RLS) for rapid & sustained effect) (IR+CR) Benzodiazepines Clonazepam RIVOTRIL,g 0.25-1mg hs $15 Hypnotic effect; limited benefit on sleep. 10 Problems with tolerance, falls, dependence RESTORIL,g 15-30mg hs $12 & daytime sedation. Antiepileptics TEGRETOL,g 200mg hs; (200 am & 400mg hs) $10-16 Limited data, maybe effective; consider if 12 Line $115 pain; CNS effects (daytime sedation, etc.) nd Gabapentin NEURONTIN,g 600-2400mg; trials:1,800mg/d

2 Valproic acid may also be effective. IR SR $60 Opioids Oxycodone IR or OXYCONTIN 5-10mg ; 10-20mg hs or q12h Maybe effective; consider if pain, or failure 20mg/d or SEs on dopamine agents; CNS effects; 27 Other options; codiene 30-180mg/day, propoxyphene DARVON 100-600mg/day, etc. ↑; dependency concern. Ac=before meals CR=controlled release HS=bedtime IR=immediate release LD=Levodopa RLS=Restless Legs Syndrome SE= side effects t1/2=half life Other options: 5-15mg/d; clonidine 0.1-1mg/d; motor disease ; amantadine; sedatives; topiramate; 0.5-2mg hs 24hr duration, but expensive; 300mg hs for leg 13 *Dosing: HS effective for most, some may require daytime (e.g. afternoon) dose. If may consider .

RLS Differential Diagnosis: ƒ Periodic limb movements of sleep (PLMS): often occurs in addition to RLS. Involves involuntary movements during sleep; brief awakenings or arousal from sleep (unaware). ƒ Nocturnal leg cramps: always involve a specific muscle; they usually require stretching of the muscle more than non-specific movement to relieve symptoms; usually unilateral ƒ Peripheral neuropathy: not usually associated with restlessness or helped by movement; does not worsen in evening or hs; sensations (numbness, tingling, or pain). May coexist ƒ Vascular disease (, deep vein thrombosis): usually accompanied by swollen legs & a change in skin color ƒ (often drug-induced): usually involves spontaneous movement of the whole body without sensory complaints; lacks a circadian pattern. ƒ Intermittent claudication: usually worsens with exercise & improves with rest. ƒ Rapid eye movement (REM) sleep behavior disorder: complex, often violent, motor behaviors associated with dreams (dream may not be recalled). Typically after age 60+ ƒ Painful legs and moving toes: rare disorder not involving an urge to move limb RLS Websites: www.rls.org; www.aasmnet.org; Specific drug comparison charts at www.RxFiles.ca; Clinical Knowledge Summary (CKS) http://www.cks.nhs.uk/ Evidence based reviews: http://www.jr2.ox.ac.uk/bandolier/booth/booths/RLS.html 66 © www.RxFiles.ca - Jan 2010 RxFiles: Q&A Summary Loren Regier BSP BA, Brent Jensen BSP

RxFiles Academic Detailing Essential Tremor (ET) & Restless Legs Syndrome (RLS) - Treatment Options Additional References: Baker WL, White CM, Coleman CI. Effect of nonergot dopamine agonists on symptoms of restless legs syndrome. Ann Fam Med. 2008 May-Jun;6(3):253-62. Bogan RK, et al.; TREAT RLS US Study Group. Ropinirole in the treatment of RLS: a US-based double-blind, placebo-controlled RCT. Mayo Clin Proc. 2006 Jan;81(1):17-27.(InfoPOEMs Apr/06). Bushara KO, Malik T, Exconde RE. The effect of levetiracetam on essential tremor. . 2005 Mar 22;64(6):1078-80. Connor GS, Edwards K, Tarsy D. Topiramate in essential tremor: findings from double-blind, placebo-controlled, crossover trials. Clin Neuropharmacol. 2008 Mar-Apr;31(2):97-103. Gao X, Schwarzschild MA, Wang H, Ascherio A. Obesity and restless legs syndrome in men and women. Neurology. 2009 Apr 7;72(14):1255-61. Both overall and abdominal adiposity are associated with increased likelihoods of having restless legs syndrome (RLS). Gironell A, Kulisevsky J, Barbanoj M, et al. A randomized placebo-controlled comparative trial of gabapentin and propranolol in essential tremor. Arch Neurol. 1999 Apr;56(4):475-80. Health Canada Aug/07: Eli Lilly Canada advises Healthcare Professionals that they will cease sale of Permax August 30, 2007 due to risk of cardiac valvulopathy. Koller WC. Propranolol therapy for essential tremor of the head. Neurology. 1984;34(8):1077-9. Lettieri CJ, Eliasson AH. Pneumatic compression devices are an effective therapy for restless legs syndrome: a prospective, randomized, double-blinded, sham-controlled trial. Chest. 2009 Jan;135(1):74- 80. Epub 2008 Nov 18. PCDs resulted in clinically significant improvements in symptoms of RLS in comparison to the use of sham devices & may be an effective adjunctive or alternative therapy for RLS. Medcalf P, Bhatia KP. Restless legs syndrome. BMJ. 2006 Sep 2;333(7566):457-8. Molnar MZ, Novak M, Mucsi I. Management of restless legs syndrome in patients on .Drugs. 2006;66(5):607-24. Ondo WG, et al.; Topiramate Essential Tremor Study Investigators. Topiramate in essential tremor: a double-blind, placebo-controlled trial. Neurology. 2006 Mar 14;66(5):672-7. Epub 2006 Jan 25. (InfoPOEMs: Topiramate (Topamax) is slightly better than placebo in improving tremor and function in patients with essential tremor. In this study, the differences do not appear to be clinically significant. Given the expense and the significant drop-out rate due to side effects, topiramate should not be used as a first-line treatment. (LOE = 1b)) Ondo W, Hunter C, Vuong KD, Schwartz K, Jankovic J. Gabapentin for essential tremor: a multiple-dose, double-blind, placebo-controlled trial. Mov Disord. 2000 Jul;15(4):678-82. Pahwa R, Lyons K, Hubble JP, Busenbark K, Rienerth JD, Pahwa A, Koller WC. Double-blind controlled trial of gabapentin in essential tremor. Mov Disord. 1998 May;13(3):465-7. Pharmacist’s Letter: Mirapex (Pramipexole) for RLS Nov/06. Reccoppa L, Malcolm R, Ware M. Gabapentin abuse in inmates with prior history of . Am J Addict. 2004 May-Jun;13(3):321-3. Sasso E, Perucca E, Calzetti S. Double-blind comparison of primidone and phenobarbitone in essential tremor. Neurology 1988;38:808–810. Sasso E, Perucca E, Fava R, Calzetti S. Quantitative comparison of in essential hand and head tremor. Mov Disord. 1991;6(1):65-8. Satija P, Ondo WG. Restless legs syndrome : pathophysiology, diagnosis and treatment. CNS Drugs. 2008;22(6):497-518 Stefansson H, Rye DB, Hicks A, et al. A genetic risk factor for periodic limb movements in sleep.N Engl J Med. 2007 Aug 16;357(7):639-47. Epub 2007 Jul 18. We have discovered a variant associated with susceptibility to periodic limb movements in sleep. The inverse correlation of the variant with iron stores is consistent with the suspected involvement of iron depletion in the pathogenesis of the disease. Trenkwalder C, et al. Controlled withdrawal of pramipexole after 6 months of open-label treatment in patients with restless legs syndrome. Mov Disord. 2006 Jun 5; [Epub ahead of print] Trenkwalder C, et al; PEARLS Study Group. Efficacy of pergolide in treatment of restless legs syndrome: the PEARLS Study. Neurology. 2004 Apr 27;62(8):1391-7. Trenkwalder C, et al.; Therapy with Ropiunirole; Efficacy and Tolerability in RLS 1 Study Group. Ropinirole in the treatment of restless legs syndrome: results from the TREAT RLS 1 study, a 12 week, randomised, placebo controlled study in 10 European countries. J Neurol Neurosurg Psychiatry. 2004 Jan;75(1):92-7. Vignatelli L, Billiard M, Clarenbach P, et al; EFNS Task Force. EFNS guidelines on management of restless legs syndrome and periodic limb in sleep. Eur J Neurol. 2006 Oct;13(10):1049-65. The following level A recommendations can be offered: for primary RLS, cabergoline, gabapentin, pergolide, ropinirole, levodopa and by transdermal delivery (the latter two for short-term use) are effective in relieving the symptoms. Transdermal oestradiol is ineffective for PLMD. Winkelman JW, Allen RP, Tenzer P, Hening W. Restless legs syndrome: nonpharmacologic and pharmacologic treatments. Geriatrics. 2007 Oct;62(10):13-6. Winkelman JW, et al. Efficacy and safety of pramipexole in restless legs syndrome. Neurology. 2006 Sep 26;67(6):1034-9. Epub 2006 Aug 23. Winkelman JW, Shahar E, Sharief I, Gottlieb DJ. Association of restless legs syndrome and cardiovascular disease in the Sleep Heart Health Study. Neurology. 2008 Jan 1;70(1):35-42. Restless legs syndrome (RLS) is associated with prevalent coronary artery disease and cardiovascular disease. This association appears stronger in those with greater frequency or severity of RLS symptoms. Zesiewicz TA, Ward CL, Hauser RA, et al.. A pilot, double-blind, placebo-controlled trial of pregabalin (Lyrica) in the treatment of essential tremor. Mov Disord. 2007 Aug 15;22(11):1660-3.

References

1 Zesiewicz TA, et al. Practice Parameter: Therapies for essential tremor. Report - American Academy of Neurology. Neurology. 2005 Jun 22 http://www.neurology.org/cgi/reprint/64/12/2008.pdf?ck=nck 2 Louis ED. Essential tremor. Lancet Neurol. 2005 Feb;4(2):100-110. 3 Smaga S. Tremor. Am Fam Physician. 2003 Oct 15;68(8):1545-52. 4 Lyons KE, Pahwa R, Comella CL, et al. Benefits and risks of pharmacological treatments for essential tremor. Drug Saf. 2003;26(7):461-81. 5 Sullivan KL, Hauser RA, Zesiewicz TA. Essential tremor. Epidemiology, diagnosis, and treatment. Neurologist. 2004 Sep;10(5):250-8. 6 Micromedix 2009. 7 Lyons KE, Pahwa R. Pharmacotherapy of essential tremor : an overview of existing and upcoming agents. CNS Drugs. 2008;22(12):1037-45. 8 Elble RJ. Tremor: clinical features, pathophysiology, and treatment. Neurol Clin. 2009 Aug;27(3):679-95, v-vi. 9 Jensen B. RxFiles Anticonvulsants Drug Chart. http://www.rxfiles.ca/rxfiles/uploads/documents/members/Cht-psyc-.pdf (Subscription required) 10 Serrano-Dueñas M. Use of primidone in low doses (250 mg/day) versus high doses (750 mg/day) in the management of essential tremor. Double-blind comparative study with one-year follow-up. Relat Disord. 2003 Oct;10(1):29-33. 11 Connor GS. A double-blind placebo-controlled trial of topiramate (Mean dose 333mg/d) treatment for essential tremor. Neurology. 2002 Jul 9;59(1):132-4. 12 Jensen B. RxFiles Drug Chart: http://www.rxfiles.ca/rxfiles/uploads/documents/members/Cht-Psyc-Benzodiazepines.pdf 13 Simpson DM, Blitzer A, Brashear A, Comella C, Dubinsky R, Hallett M, Jankovic J, Karp B, Ludlow CL, Miyasaki JM, Naumann M, So Y; Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Assessment: Botulinum for the treatment of movement disorders (an evidence-based review): report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology. 2008 May 6;70(19):1699-706. 14 Bushara KO, Malik T, Exconde RE. The effect of levetiracetam on essential tremor. Neurology. 2005 Mar 22;64(6):1078-80. 15 Thorpy MJ. New paradigms in the treatment of restless legs syndrome. Neurology. 2005 Jun 28;64(12_suppl_3):S28-S33. 16 Allen RP, Picchietti D, Hening WA, et al; Restless Legs Syndrome Diagnosis and Epidemiology workshop at the NIH. Sleep Med. 2003 Mar;4:101-19. 17 Chaudhuri KR, Forbes A, Grosset D, et al.. Diagnosing restless legs syndrome (RLS) in primary care. Curr Med Res Opin. 2004 Nov;20(11):1785-95. 18 2004 Restless Legs Syndrome Foundation Bulletin. Accessed June 02, 2005 @ http://www.rls.org/literature/bulletin.html 19 Silber MH, Ehrenberg BL, Allen RP, et al. An algorithm for the management of restless legs syndrome. Mayo Clin Proc. 2004 Jul;79(7):916-22. 20 Micromedix 2009; and Micromedix Drug Consults – Restless Legs Syndrome – Drugs of Choice Dec 2002. 21 Happe S, Trenkwalder C. Role of agonists in the treatment of restless legs syndrome. CNS Drugs. 2004;18(1):27-36. 22 Pharmacists Letter June 2005 – Treatment of Restless Legs Syndrome. 23 Hening WA, Allen RP, Earley CJ, et al. Restless Legs Syndrome Task Force of the Standards of Practice Committee of the American Academy of . An update on the dopaminergic treatment of restless legs syndrome and periodic limb movement disorder. Sleep. 2004May 1;27(3):560-83. 24 Earley CJ. Clinical practice. Restless legs syndrome. N Engl J Med. 2003 May 22;348(21):2103-9. 25 Manconi M, Govoni V, De Vito A, Economou NT, et al. Restless legs syndrome and pregnancy. Neurology. 2004 Sep 28;63(6):1065-9. 26 Jensen B. RxFiles Parkinson’s Drug Chart: http://www.rxfiles.ca/rxfiles/uploads/documents/members/Cht-Parkinson.pdf (Subscription required.) 27 Regier L. RxFiles Opioid Drug Chart. http://www.rxfiles.ca/rxfiles/uploads/documents/members/CHT-Opioid.pdf (Subscription required.); Newsletter: http://www.rxfiles.ca/rxfiles/uploads/documents/Pain-Chronic-NonCa-NEWSLETTER-Header.pdf ; Opioid Sample Treatment Agreement: http://www.rxfiles.ca/rxfiles/uploads/documents/Pain-CNMP-Opioid-TreatmentAGREEMENT.doc

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Acknowledgement of Reviewers: • Dr. Alex Rajput, Neurology, University of Saskatchewan, Saskatoon, SK; Dr. Carol Boyle, Neurology, Saskatoon, SK; RxFiles Advisory Committee

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