Bupropion-Induced Neck and Shoulder Pain

Bupropion is an antidepressant drug in the aminoketone class that selectively inhibits the reuptake of both dopamine and norepinephrine. The elimination half-life of extended-release bupropion is approximately 21 h; half-lives for the three active metabolites are 20–37 h [2]. A once-daily extended-release formulation was approved in August of 2003 for the treatment of major depression in adults. All three available formulations of bupropion, i. e., immediate, sustained, and extended release, demonstrate equivalence with regard to peak plasma concentrations and area under the curve. In the following case report, we describe an uncommon muscular reaction, which occurred following an increase in the dosage of bupropion extended release.

Mrs. L. was a 75-year-old white female with major depression who, following unremarkable treatment trials with two SSRIs, duloxetine, and venlafaxine extended release, was prescribed bupropion extended release 150 mg per day in April of 2008. She had an initial positive response (“I’m feeling much better!”) without any over-stimulation (i. e., anxiety, insomnia, jitteriness, night sweats). In June of 2008, the patient wished to explore the potential mood effects of an increase in bupropion extended release to maximize her overall response. She was prescribed bupropion extended release 300 mg per day and “did great for the first few days.” However, on day 5 of the 300-mg dose, the patient began to experience in her neck and between her shoulders a constant muscular ache, which worsened with movement and disturbed her sleep. Affected areas were painful to touch and the patient rated the pain level at 6/10 on an analogue scale from 1 (no pain) to 10 (extreme pain). The pain was unresponsive to treatment with a heating pad or ibuprofen. After 2 weeks of unrelenting neck and shoulder myalgia, the patient suspected the bupropion extended release as causal. She lowered the dose to 150 mg per day and the symptoms promptly receded within 48 h.

In addition to bupropion extended release, Mrs. L. was prescribed several non-psychotropic medications for various medical indications (i. e., seasonal allergies, gastro-esophageal reflux, hypertension, hypothyroidism, hypercholesterolemia) including cetirizine (Zyrtec), mometasone (Nasonex), esomeprazole (Nexium), amlodipine (Norvasc), levothyroxine (Synthroid), and atorvastatin (Lipitor). During the trial with bupropion extended release, the doses of these medications were stable and unchanged for months.

The temporal relationship between dose increase of the antidepressant and the onset of the patient's myalgias as well as the half-life of the drug strongly implicate bupropion extended release as the causal factor. While the underlying pathophysiology remains unknown, in clinical trials, bupropion was associated with both neck pain (2%) and myalgia (2%), which each capture the observed adverse effects described by this patient [8].

In addition to the preceding adverse side effects, unusual neuromuscular side effects with bupropion, with their own unique etiologies, have been reported in the literature. For example, there are several case reports that describe acute dystonias with bupropion exposure (e. g., bilateral trismus, inability to rotate one's head laterally, oro-facial dystonia) [3] [4] [7]. Iskandar and colleagues [6] described a case of bupropion-related rhabdomyolysis, which was associated with an elevation in CPK levels but not with focalized muscle pain. Finally, Bagshaw and colleagues [1] describe the case of a 24-year-old male who was prescribed bupropion sustained release and, in the course of a complicated reaction, developed non-specific myalgias in his thighs.

Importantly, in this particular case, there may have been several contributory factors in the evolution of these symptoms. First, bupropion and its metabolites may accumulate in the elderly, enhancing the benefits as well as side-effect risks [8].

Second, the adverse effects may have been enhanced by the co-administration of amlodipine. Bupropion is metabolized via the cytochrome P450 2B6, an enzyme that is potentially inhibited by amlodipine. Through inhibition, levels of the antidepressant may have increased, resulting in a higher risk for adverse side effects.

Finally, the patient may have been a slow metabolizer of bupropion. Cytochrome P450 2B6 is subject to genetic variation [5] and if slow metabolism was occurring, then the levels of bupropion in this patient would have been enhanced, contributing to the unusual muscular effects.

To summarize, while uncommon, bupropion may be associated with muscle symptoms – including myalgias. Several factors may have enhanced the risk of this adverse side effect in this particular case (i. e., “the perfect storm”), including the patient's age, co-administration of a medication that may have inhibited cytochrome P-450 2B6, and the possibility of a genetically slow 2B6 enzyme. With this type of adverse reaction, because of bupropion's short half-life, a dose reduction or discontinuation of the antidepressant is likely to promptly ameliorate muscle symptoms in 24–48 h.

References

• 1 Bagshaw SM, Cload B, Gilmour J. et al . Drug-induced rash with eosinophilia and systemic symptoms syndrome with bupropion administration.  Ann Allergy Asthma Immunol. 2003;  90 572-575
• 2 Clinical Psychopharmacology. Tampa, Florida: Gold Standard 2008
• 3 Detweiler MB, Harpold GJ. Bupropion-induced acute dystonia.  Ann Pharmacother. 2002;  36 251-254
• 4 Hernanz Hernanz P, Ortega Inclan M, Sainza Rua T. et al . Dystonia associated with bupropion.  Aten Primaria. 2001;  28 507-508
• 5 Hesse LM, He P, Krishnaswamy S. et al . Pharmacogenetic determinants of interindividual variability in bupropion hydroxylation by cytochrome P450 2B6 in human liver microsomes.  Pharmacogenetics. 2004;  14 225-238
• 6 Iskandar SB, Brahmbhatt VR, al Hasan MA. et al . Muscle injury associated with bupropion therapy.  Tenn Med. 2003;  96 471-472
• 7 Milton JC, Abdulla A. Prolonged oro-facial dystonia in a 58 year old female following therapy with bupropion and St Johns wort.  Br J Clin Pharmacol. 2007;  64 717-718
• 8 Zyban prescribing information . Located at. http://us.gsk.com/products/assets/us_zyban.pdf , Accessed on 1/12/09

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