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The psychiatric prescribing clinician may be called upon to treat pain comorbid with bipolar disorder.
Do you think of duloxetine when your patient with depression (bipolar or otherwise) reports chronic pain? The psychiatric prescribing clinician may be called upon to prescribe medication for the pain or may be asked by the primary care clinician or pain clinic if certain pain medications would be acceptable considering bipolar comorbidity. Or, those clinicians may go ahead and prescribe duloxetine or amitriptyline without even notifying you.
A previous column1 discussed that antidepressants, especially serotonin-norepinephrine reuptake inhibitors (SSRIs) and tricyclics, are generally ill-advised for patients with bipolar disorder because of the risks of increasing cycling, especially to depression and, over the long term, to mania—even when added to a mood stabilizer.2.3
Although some antidepressants (eg, duloxetine) are approved by the US Food and Drug Administration for use in pain syndromes like fibromyalgia, diabetic neuropathy, and chronic musculoskeletal pain, it is also important to recognize the evidence shows they are minimally effective in addressing pain in patients with depression. The great majority of patients in studies of these pain conditions were not depressed. Four meta-analyses reviewed by Gebhardt and colleagues4 have evaluated the effect of antidepressants on pain in patients with depression. The effect size of antidepressants versus placebo on comorbid pain in patients with depression is very small and usually clinically insignificant, regardless of the antidepressant used. Duloxetine, notably, did not stand out as any more effective than the others (tricyclics, paroxetine, venlafaxine, other SSRIs). We are talking about duloxetine reducing pain by 12% to 27% more than placebo reduced it—a difference that does not seem meaningful.
Duloxetine was extensively marketed based upon its FDA indications for pain management treatment and became a multi-billion-dollar product (until its patent expired and it became generic), but review authors concluded that this economic activity was not justified by the evidence. There is no reason to think of it as the go-to medication for a depressed patient with pain difficulties. Further, a Cochrane review of depression studies found that the dropout rate with duloxetine was higher than with escitalopram or venlafaxine, possibly due to greater adverse effects.5 If the patient is not depressed and has these pain syndromes, duloxetine may play a role. The meta-analyses did find a correlation between improvement in depression and improvement in pain.4 This suggests that choosing medications (unlike duloxetine) that work in bipolar depression (eg, FDA-approved options) may result in some improvement in pain.
Cannabis is being considered for treatment of pain as an alternative to opioids.6 We discussed in the April 2020 column the significant evidence that cannabis causes more cycling and destabilization in patients with bipolar disorder, and that it is without an evidence-base for pain.7 It is, therefore, irresponsible to encourage patients with severe pain and opiate misuse problems to consider cannabis as a viable treatment.
Medications with reasonable evidence of modest efficacy for pain that do not exacerbate symptoms of bipolar disorder include acetaminophen; non-steroidal anti-inflammatory agents (stronger than acetaminophen—but be careful about the interaction with lithium to raise lithium levels); gabapentin (no efficacy for mood swings, though); pregabalin (may work when gabapentin fails, possibly because of genetically based transporter-related interactions); and carbamazepine (for trigeminal neuralgia and possibly other kinds of pain). It should be stressed that there are many non-pharmacological strategies for pain management, such as mindfulness training, physical activity and therapy, massage, and acupuncture (Table).
Dr Osser is associate professor of psychiatry, Harvard Medical School, and consulting psychiatrist, US Department of Veterans Affairs, National Telemental Health Center, Bipolar Disorders Telehealth Program, Brockton, MA. He is a member of the Psychiatric TimesTM Editorial Board. The author reports no conflicts of interest concerning the subject matter of this article.
1. Osser DN. The Case Against Antidepressants for Bipolar Depression: Findings from STEP-BD. Psychiatric Times. 2020;37(6):29.
2. McGirr A, Vöhringer PA, Ghaemi SN, et al. Safety and efficacy of adjunctive second-generation antidepressant therapy with a mood stabilizer or an atypical antipsychotic in acute bipolar depression: a systematic review and meta-analysis of randomized placebo-controlled trials. Lancet Psychiatry. 2016:3:1138-1146.
3. El-Mallakh RS, Vöhringer PA, Ostacher MM, et al. Antidepressants worse rapid cycling course in bipolar depression: a STEP-BD randomized clinical trial. J Affect Disord. 2015;184:318-321.
4. Gebhardt S, Heinzel-Gutenbrunner M, König U. Pain relief in depressive disorders: a meta-analysis of the effects of antidepressants. J Clin Psychopharmacol. 2016;36(6):658-668.
5. Cipriani A, Koesters M, Furukawa TA, et al. Duloxetine versus other anti-depressive agents for depression. Cochrane Database Syst Rev. 2012;10:CD006533.
6. Humphreys K, Saitz R. Should physicians recommend replacing opioids with cannabis? JAMA. 2019;321(7):639-640
7. Osser DN. Cannabis: Patients With Bipolar Should Avoid Use. Psychiatric Times. 2020;37(4):25.❒