NON-OPIOID TREATMENT OPTIONS FOR CHRONIC PAIN Alison Knutson, PharmD, BCACP Medication Management Pharmacist Park Nicollet Creekside Clinic Dr. Knutson indicated no potential conflict of interest to this presentation. She does not intend to discuss any unapproved/investigative use of a commercial product/device. IF I M NOT TREATING WITH OPIOIDS, THEN WHAT AM I SUPPOSED TO USE?
Objectives Review the types of pain Evaluate adjunctive treatment options based on pain type Other special considerations
Why non-opioid analgesics Improve pain management Eliminate the need for opioids Enhance the opioid analgesia Provide analgesia through non-opioid (and therefore likely lower risk) mechanisms of action
NEUROPATHIC NOCICEPTIVE Neuropathic vs. Nociceptive Pain Neuropathic pain has higher pain scores and lower HRQOL (health-related quality of life) Improvement of >30% is considered significant for neuropathic pain, >50% for nociceptive Often require more medications and receive less pain relief from treatment
PARTNERING THE SOURCE WITH THE TREATMENT Neuropathic Pain What is the evidence?
Neuropathic Pain Treatment Per Neuropathic Pain Special Interest Group (NeuSIG), Canadian Pain Society (CPS) and European Federation of Neurological Societies (EFNS) Evidence supports: SNRI (duloxetine, venlafaxine) TCA (nortriptyline, amitriptyline) Calcium Channel Ligands (gabapentin, pregabalin) Opioids, tramadol, and topical lidocaine are SECOND line SNRI: Duloxetine or venlafaxine? Duloxetine Indicated for diabetic neuropathy, fibromyalgia, chronic musculoskeletal pain Well tolerated: nausea with initiation Head to head trial vs. amitriptyline: equivalent outcomes Venlafaxine Lower doses have not shown significance when compared to placebo At doses <150mg/day, acts only as an SSRI A Comparative Evaluation of Amitriptyline and Duloxetine in Painful Diabetic Neuropathy. Diabetes Care. 2011 Apr; 34(4): 818 822.
TCA: Nortriptyline or amitriptyline? Therapeutically interchangeable? More robust evidence for amitriptyline, flawed studies for others Theoretical superior pharmacology with nortriptyline? Tolerability: secondary amines preferred (ie. nortrip, desipramine) Less anticholinergic: dry mouth, dry eyes, constipation, urinary retention ischemic cardiac disease or ventricular conduction abnormalities Consider screening EKG for pts >40yo per NeuPSIG Guidelines TCAs shown NOT effective in HIV or chemo-associated neuropathy Recommendations for the Pharmacological Management of Neuropathic Pain: An Overview and Literature Update. Dworkin et. al. Mayo Clin Proc. 2010 Mar; 85(3). Gillman, P. Tricyclic antidepressant pharmacology and therapeutic drug interactions updated. British Journal of Pharmacology (2007) 151, 737 748 Gabapentin or pregabalin? Gabapentin Pregabalin Same mechanism of action- which is not GABA! Bioavailability 33-66% 80-90% Pharmacokinetics Non-linear (especially at higher doses) Linear Clinical Trials? Mostly off-label use Many more studies available Potency (via EC50- lower is better) 11.7 mg/ml 4.21 mg/ml (2.8 times MORE potent) Bockbrader HN, A comparison of the PK and PD of pregabalin and gabapentin. Clin Pharmacokinet. 2010;49(10):661-9. Toth C. Substitution of gabapentin with pregabalin in neuropathic pain due to peripheral neuropathy. Pain Med. 2010;11(3):456-65.
Other Anticonvulsants? Pain Condition Effective Ineffective Trigeminal Neuralgia Carbamazepine, Oxcarbazepine, Lamotrigine Fibromyalgia Pregabalin, gabapentin Lacosamide, Pheytoin Diabetic peripheral neuropathy Post-herpetic neuralgia HIV-associated neuropathy CRPS Type I Spinal cord injury neuropathy Pregabalin, gabapentin, oxcarbazepine, carbamazepine, sodium valproate Pregabalin, gabapentin, carbamazepine, sodium valproate Lamotrigine, gabapentin Lamotrigine Pregabalin, gabapentin Acute and chronic pain??? Lamotrigine Pain: Assessment, Non-Opioid Treatment Approaches and Opioid Management Algorithm. ICSI. Seventh Edition/September 2016. Class Medication Recommendatio Starting dose Max dose Adequate Trial Side Effects Precautions n TCA Nortriptyline First Line 25mg qhs Increase 25mg/day 4-6 weeks (>2 Sedation, dry mouth, blurred Cardiac disease, seizure (or Amitriptyline) every 5 days up to weeks at max vision, urinary retention disorder, use with tramadol 150mg/day tolerable dose) Ca ++ channel α 2 - δ ligands Gabapentin First Line 100-300mg qhs or TID Increase by 100-300mg every 3-7 days, up to 3600mg/day Pregabalin First Line 50mg TID or 75mg BID Increase every 3-7 days up to 300mg/day* SSNRI Duloxetine First Line 30mg once daily Increase to 60mg/day after 1 week 3-8 weeks for titration, (>2 weeks at max tolerable dose) Sedation, dizziness, peripheral edema 4 weeks Sedation, dizziness, peripheral edema Dose adjusted for renal impairment Dose adjusted for renal impairment 4 weeks Nausea, sedation Hepatic or renal insufficiency, use with tramadol Venlafaxine (>150mg/day) First Line 37.5mg once daily or BID Increase 75mg/week until relief, or 225mg/day 4-6 weeks nausea Cardiac disease, seizure disorder, use with tramadol Topical Lidocaine Lidoderm 5% patch, oint. First Line for Localized pain Apply 1-3 patches 3 patches/12 hours each 3 weeks Local irritation, rash None Opioid Agonists Oxycodone Morphine Second Line** Second Line** 5mg q 6hr or PRN 10-15mg q 4hr or PRN Can convert total daily dose to LA after 1-2 weeks, maintain short acting as breakthrough 4-6 weeks Constipation, drowsiness, dizziness History of substance abuse, long term use Tramadol Second Line** 50mg once or twice daily Increase 50-100mg/day every 3-7 days up to 400mg/day 4 weeks Constipation, drowsiness, dizziness, seizures Use with serotonergic drugs (SSRI, SNRI), age >75 max dose is 300mg
Milnacipran (SAVELLA ) MOA: selective serotonin and norepinephrine reuptake inhibitor blocks the reuptake of norepinephrine over serotonin with approximately 3 times greater potency in vitro Indication: fibromyalgia Off-label for depression Limitations: cost In clinical trial was superior to placebo, not studied against other therapies Nociceptive Pain What is the evidence?
Musculoskeletal Pain Not medications? PT, injections, surgery, etc. TCAs, duloxetine Muscle Relaxant Limited treatment length (2-3 weeks) Cyclobenzaprine (5-10mg TID) Tizanidine (2-8mg TID) Depression and pain Other antidepressants (with limited evidence Inflammatory Pain Corticosteroids NSAIDs (oral and topical) Class Advantages Disadvantages APAP May decrease opioid requirement Lack of anti-platelet effects Lack of GI effects Cheap, OTC Weak to no anti-inflammatory action Liver dysfunction Max dose 3-4g/day (depending on patient) NSAIDs May decrease opioid requirement Strong anti-inflammatory Renal dysfunction (limiting, and may cause it) Bleeding risk (platelet effects) GI Ulcer
Topical NSAIDs OTC: methylsalicylate patch, cream Rx: Diclofenac topical solution (Pennsaid), 1% gel (Voltaren Gel), topical patch (Flector) What about cardiovascular and GI risk? Systemic absorption is a fraction of oral NSAID
Money Money Money Money! Most medications available as generic Biggest limitation for med selection is likely drug interactions and cost Lidocaine Patch: often ONLY covered for PHN However: OTC lidocaine 4% patch GoodRx or $4 lists for medication prices pain neuropathic nociceptive SNRI (duloxetine, venlafaxine) TCA (amitriptyline, nortriptyline) Ca++ Ligand (gabapentin, pregabalin) Lidocaine Second line: opioids, tramadol TCAs, duloxetine cyclobenzaprine tizanidine corticosteroids NSAIDs
QUESTIONS? Alison.Knutson@parknicollet.com References Attal N, Cruccu G, Baron R, et al. EFNS guidelines on the pharmacological treatment of neuropathic pain: 2010 revision. Eur J Neurol 2010;17:1113-e88. Bockbrader HN, A comparison of the PK and PD of pregabalin and gabapentin. Clin Pharmacokinet. 2010;49(10):661-9. Dworkin RH, O'Connor AB, Audette J, et al. Recommendations for the pharmacological management of neuropathic pain: an overview and literature update. Mayo Clin Proc 2010;85:S3-14. Dworkin RH, O'Connor AB, Backonja M, et al. Pharmacologic management of neuropathic pain: evidence-based recommendations. Pain 2007;132:237-51. Fudin, J. How Gabapentin Differs From Pregabalin. Pharmacy Times, September 21, 2015. Haanpaa M, Attal N, Backonja M, et al. NeuPSIG guidelines on neuropathic pain assessment. Pain 2011;152:14-27. Haanpaa ML, Backonja MM, Bennett MI, et al. Assessment of neuropathic pain in primary care. Am J Med 2009;122:S13-21. Moulin DE, Clark AJ, Gilron I, et al. Pharmacological management of chronic neuropathic pain - consensus statement and guidelines from the Canadian Pain Society. Pain Res Manag 2007;12:13-21. Toth C. Substitution of gabapentin with pregabalin in neuropathic pain due to peripheral neuropathy. Pain Med. 2010;11(3):456-65. Choosing a Skeletal Muscle Relaxant. Am Fam Physician. 2008;78(3):365-370 Pain: Assessment, Non-Opioid Treatment Approaches and Opioid Management Algorithm. Institute for Clinical Systems Improvement. Seventh Edition/September 2016. A Comparative Evaluation of Amitriptyline and Duloxetine in Painful Diabetic Neuropathy. Diabetes Care. 2011 Apr; 34(4): 818 822.