Savvy Psychopharmacology When to prescribe antidepressants to treat comorbid depression and pain 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 chronic pain 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 medication rate diagnosis. To decrease polypharmacy regimen includes losartan, 100 mg/d; atenolol, and pill burden, optimal treatment should 25 mg/d; gabapentin, 100 mg, 3 times a day; employ agents that treat both conditions. Vicki L. Ellingrod, sertraline, 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 opioids 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 • fibromyalgia of her arm, shoulder, neck, and chest. Ms. C • diabetic neuropathy reports poor quality of sleep and early morn- • neuropathic pain ing awakenings, which she attributes to her • postherpetic neuralgia 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 serotonin reuptake Pharmacy, University of Southern California School of Pharmacy, mhc.cpnp.org (journal) Los Angeles, California. inhibitor to either a serotonin- norepinephrine reuptake inhibitor or Disclosures The authors report no financial relationship with any company whose tricyclic antidepressant 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 Venlafaxine XR Diabetic neuropathy No 37.5 to 225 mg/d2 Fluoxetine 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 Duloxetine 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 Imipramine Neuropathic pain No 50 to 150 mg/d5 Amitriptyline 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; Nortriptyline 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 Postherpetic neuralgia No 10 to 160 mg/d Desipramine 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 milnacipran.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-enantiomer, levomilnacipran, is. Unlike triptyline, imipramine, and desipramine.14 duloxetine and venlafaxine, both milnacip- TCAs are cost-effective medications 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 analgesics. 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 Ketamine • 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, paroxetine, and citalopram 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, placebo- 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