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Home , Milnacipran, Neuropathic pain

Savvy Psychopharmacology

When to prescribe to treat comorbid depression and disorders

Andrew M. Williams, PharmD, BCPP, CGP, and Erin D. Knox, PharmD, BCPP

s. C, age 44, has a history of hyper- ized aches, frequent headache, and fatigue, tension, chronic shoulder pain many of which overlap with Massociated with a motor vehicle disorders. Therefore, a thorough symptom accident almost 2 decades ago, and major assessment and history is vital for an accu- depressive disorder (MDD). Her rate diagnosis. To decrease polypharmacy regimen includes losartan, 100 mg/d; atenolol, and pill burden, optimal treatment should 25 mg/d; , 100 mg, 3 times a day; employ agents that treat both conditions. Vicki L. Ellingrod, , 100 mg/d; and naproxen, 500 mg, PharmD, FCCP twice a day as needed for pain. She does Using antidepressants to treat Department Editor not take for pain control because pain disorders she had a poor response when used in the Several antidepressants have been studied past. Ms. C denies muscle pain or tender- for managing pain disorders including: ness but describes pain in nonspecific areas • of her arm, shoulder, neck, and chest. Ms. C • reports poor quality of and early morn- • ing awakenings, which she attributes to her • postherpetic unmanaged pain. Her last appointment with • migraine prophylaxis a psychiatrist was “many, many months ago.” • chronic musculoskeletal pain. Antidepressants that treat both depression A reciprocal relationship exists between and chronic neuropathic pain include tricy- depression and pain. A 2-year, population- based, prospective, observational study of Practice Points 3,654 patients showed that pain at baseline • Many physical symptoms reported by patients was an independent predictor of depression with depression, such as constipation, and a depression diagnosis was a predictor heightened pain sensitivity, and/or frequent of developing pain within 2 years.1 Patients headaches, overlap with chronic painful with MDD might complain of physical conditions and distinguishing symptoms may prove difficult. symptoms, such as constipation, general- • In patients who may have comorbid Dr. Williams is Clinical Pharmacist, Riverside University Health Savvy Psychopharmacology System, Riverside, California, Adjunct Assistant Professor of Clinical depression and pain first assess for is produced in partnership Pharmacy, University of Southern California School of Pharmacy, depressive symptomatology, then evaluate with the College and Adjunct Assistant Professor of Pharmacy Practice, University of symptoms attributed to chronic pain. of Psychiatric the Pacific Thomas J. Long School of Pharmacy and Health Sciences. and Neurologic Dr. Knox is Clinical Pharmacist, Keck Medical Center of University • Recent literature supports switching Pharmacists cpnp.org of Southern California, and Adjunct Assistant Professor of Clinical from a selective Pharmacy, University of Southern California School of Pharmacy, mhc.cpnp.org (journal) Los Angeles, California. inhibitor to either a serotonin- or Disclosures The authors report no financial relationship with any company whose in patients with products are mentioned in this article or with manufacturers of neuropathic pain and depression. Current Psychiatry competing products. Vol. 16, No. 1 55 Savvy Psychopharmacology

Table Antidepressants used to treat pain disorders Medication Use FDA-approval Dosing XR Diabetic neuropathy No 37.5 to 225 mg/d2 Fibromyalgia No Initial 20 mg/d, up to 80 mg/d. Mean dosage in clinical trials 45 mg/d (20 to 80 mg/d)3 Diabetic neuropathy Yes 60 mg/d (dosages >60 mg/d showed no benefit)4 Fibromyalgia Yes 30 to 60 mg/d4 Chronic musculoskeletal pain Yes 30 to 60 mg/d4 Clinical Point Neuropathic pain No 50 to 150 mg/d5 Diabetic neuropathy No 25 to 100 mg/d5 Most TCAs and SNRIs Chronic pain management No 25 to 150 mg/d6 are used off-label Migraine prophylaxis No 10 to 150 mg/d7 for pain disorders; Chronic pain No 10 to 150 mg/d8 duloxetine is the Myofascial pain No 12.5 to 35 mg/d9 only medication Orofacial pain No 10 to 100 mg/d10 11 indicated for pain No 10 to 160 mg/d Neuropathic pain No 25 to 150 mg/d12 disorders and MDD XR: extended-release

clic antidepressants (TCAs) and serotonin- the dosages used for pain tend to be lower norepinephrine reuptake inhibitors (SNRIs) than those typically used for depression. (Table).2-12 Notably, most antidepressants TCAs are not commonly prescribed for studied for pain management are used depression because of their side-effect pro- off-label; duloxetine is the only medica- file and poor tolerability. TCAs are contrain- tion with an FDA indication for MDD and dicated in patients with cardiac conduction pain disorders. abnormalities, epilepsy, and narrow-angle The hypothesized mechanism of action glaucoma. Common adverse effects include is dual serotonin and norepinephrine dry mouth, sweating, dizziness, orthostatic reuptake inhibition, based on the mono- hypotension, sedation, weight gain, urinary amine hypothesis of depression and pain retention, and constipation. These adverse signaling dysfunction in neuropathic pain. effects limit their use and have organi- Antidepressants, such as TCAs and SNRIs, zations, such as the American Geriatric address pain by increasing the synaptic Society, to caution against their use in geri- concentration of norepinephrine and/or atric patients. serotonin in the dorsal horn, thereby inhib- Discuss this article at iting the release of excitatory neurotrans- SNRIs that have been studied for pain dis- www.facebook.com/ mitters and blunting pain pathways.13 orders include venlafaxine, duloxetine, CurrentPsychiatry and .2 Of note, milnacipran TCAs used to treat comorbid depression and is not FDA-approved for MDD, but its pain conditions include amitriptyline, nor- L-, , is. Unlike triptyline, imipramine, and desipramine.14 duloxetine and venlafaxine, both milnacip- TCAs are cost-effective for man- ran and levomilnacipran are not available Current Psychiatry 56 January 2017 aging neuropathy and headache; however, as a generic formulation, therefore they Savvy Psychopharmacology

have a higher patient cost. The SNRI dos- ages used for pain management tend to be Related Resources similar to those used for MDD, indicating • Lunn MP, Hughes RA, Wiffen PJ. Duloxetine for treating painful neuropathy, chronic pain or fibromyalgia. that the target dosage may be effective for Cochrane Database Syst Rev. 2014;(1):CD007115. doi: both depressive and pain symptoms. 10.1002/14651858.CD007115.pub3. • McCleane G. Antidepressants as . CNS Drugs. 2008;22(2):139-156. Selective serotonin reuptake inhibitors Drug Brand Names (SSRIs). Compared with data available Amitriptyline • Elavil Losartan • Cozaar supporting the use of TCAs and SNRIs Atenolol • Tenormin • Ketalar for pain management, the data for SSRI Duloxetine • Cymbalta Milnacipran • Savella Desipramine • Norpramin Naproxen • Aleve, Naprosyn are sparse. Studies have evaluated fluox- Fluoxetine • Prozac Nortriptyline • Pamelor etine, , and for pain, Gabapentin • Neurontin Sertraline • Zoloft with the most promising data supporting Imipramine • Tofranil Venlafaxine XR • Effexor XR Clinical Point Levomilnacipran • Fetzima 2 fluoxetine. Fluoxetine, 10 to 80 mg/d, has Switching from a been evaluated in randomized, - controlled trials for pain conditions, includ- SSRI to duloxetine ing fibromyalgia (n = 3), painful diabetic Studies support the decision to change has been shown to neuropathy (n = 1), and facial pain (n = 1). Ms. C’s medication from sertraline to dulox- be effective when Fluoxetine was more effective than placebo etine, despite an inadequate therapeutic trial targeting pain at controlling pain in 2 fibromyalgia studies of the SSRI. symptoms with (dosage range, 10 to 80 mg/d) and 1 facial pain study (dosage, 20 mg/d).2 Using pain medication to treat comorbid MDD depression CASE CONTINUED Conversely, the use of pain medications to When evaluating potential treatment treat depression also has been studied. The options, it is noted that Ms. C is prescribed most notable data supports the use of ket- sertraline, 200 mg/d, but has been taking a amine, an anesthetic. IV ketamine is well lower dosage. Ms. C states that she has been documented for treating pain and, in recent taking sertraline, 100 mg every morning, years, has been evaluated for MDD in several for months, and noticed some minor initial small studies. Results show that IV ketamine, improvements in mood, but still has days 0.5 mg/kg, produced a rapid response in when she don’t feel like doing anything. She depressed patients.16 For pain conditions fills out a depression rating scale classify- studies support the use of ketamine as an IV ing her current depression as moderately push, continuous infusion, intermittent infu- severe. Today she rates her pain as 7 out of sion, as well as oral administration, for many 10. Suboptimal control of her depression conditions, including acute and postopera- may require a dosage increase; however, per- tive pain, chronic regional pain, and neuro- haps a change in therapy is warranted. It may pathic pain. However, there is little evidence be prudent to switch Ms. C to an SNRI, such evaluating ketamine’s effect on both pain as duloxetine, an agent that can address her scores and depression symptoms in patients depression and provide additional benefits such as Ms. C. of pain control. Switching from a SSRI to duloxetine has References 1. Chou KL. Reciprocal relationship between pain and depression been shown to be effective when targeting in older adults: evidence from the English Longitudinal Study pain symptoms in patients with comorbid of Ageing. J Affect Disord. 2007;102(1-3):115-123. 2. Lee YC, Chen PP. A review of SSRIs and SNRIs in neuropathic MDD. In addition, improvements in pain pain. Expert Opin Pharmacother. 2010;11(17):2813-2825. scores have been seen after a switch to 3. Arnold LM, Hess EV, Hudson JI, et al. A randomized placebo- duloxetine in patients with depression with controlled, double-blind, flexible-dose study of fluoxetine in the treatment of women with fibromyalgia. Am J Med. Current Psychiatry nonresponse or partial response to a SSRI.15 2002;112(3):191-197. Vol. 16, No. 1 57 continued Savvy Psychopharmacology

4. Cymbalta [package insert]. Indianapolis, IN: Eli Lily and 10. Romero-Reyes M, Uyanik JM. Orofacial pain management: Company; 2015. current perspectives. J Pain Res. 2014;7:99-115. 5. Bril V, England J, Franklin GM, et al; American Academy of 11. Raja SN, Haythornthwaite JA, Pappagallo M, et al. Opioids ; American Association of Neuromuscular and versus antidepressants in postherpetic neuralgia: a Electrodiagnostic Medicine; American Academy of Physical randomized, placebo-controlled trial. Neurology. 2002;59(7): Medicine and Rehabilitation. Evidence-based guideline: 1015-1021. treatment of painful diabetic neuropathy: report of the 12. Dworkin RH, O’Connor AB, Backonja M, et al. American Academy of Neurology, the American Association Pharmacologic management of neuropathic pain: evidence- of Neuromuscular and Electrodiagnostic Medicine, and the based recommendations. Pain. 2007;132(3):237-251. American Academy of Physical Medicine and Rehabilitation. Neurology. 2011;76(20):1758-1765. 13. Argoff C. Mechanisms of pain transmission and pharmacologic 6. McQuay HJ, Carroll D, Glynn CJ. Low dose amitriptyline in the management. Curr Med Res Opin. 2011;27(10):2019-2031. treatment of chronic pain. Anaesthesia. 1992;47(8):646-652. 14. Haanpää ML, Gourlay GK, Kent JL, et al. Treatment 7. Evers S, Afra J, Frese A, et al; European Federation of considerations for patients with neuropathic pain and other Neurological Societies. EFNS guideline on the drug treatment medical comorbidities. Mayo Clin Proc. 2010;85(suppl of migraine—revised report of an EFNS task force. Eur J 3):S15-S25. Neurol. 2009;16(9):968-981. 15. Perahia DGS, Quail D, Desaiah D, et al. Switching to 8. Atkinson JH, Slater MA, Williams RA, et al. A placebo- duloxetine in selective serotonin reuptake inhibitor non- and controlled randomized of nortriptyline for chronic partial-responders: effects on painful physical symptoms of . Pain. 1998;76(3):287-296. depression. J Psychiatric Res. 2009;43(5):512-518. 9. Haviv Y, Rettman A, Aframian D, et al. Myofascial pain: an 16. Caddy C, Amit BH, McCloud TL, et al. Ketamine and other Clinical Point open study on the pharmacotherapeutic response to stepped glutamate modulators for depression in adults. treatment with tricyclic antidepressants and gabapentin. J Oral Cochrane Database Syst Rev. 2015;(9):CD011612. doi: Use of pain Facial Pain Headache. 2015;29(2):144-151. 10.1002/14651858.CD011612.pub2. medications for depression has been studied, but there’s little evidence on its effect in patients such as Ms. C

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