What causes hyperhidrosis in patients taking orexin receptor antagonists, such as suvorexant (Belsomra), and how is it managed?

Profuse Sweating with Orexin Inhibitors: Frequency and Cause

Profuse sweating is not a commonly reported adverse effect of orexin receptor antagonists like suvorexant, occurring in less than 7% of patients, with somnolence being the predominant side effect. 1, 2, 3

Frequency of Hyperhidrosis with Orexin Inhibitors

• The most common adverse effect of suvorexant is somnolence, occurring in approximately 7% of patients (versus 3% for placebo), not hyperhidrosis. 1, 4
• Clinical trials of suvorexant at doses of 10-20 mg have not identified profuse sweating as a primary adverse effect in the safety profile. 3, 5
• The FDA labeling for suvorexant warns primarily of cognitive and behavioral changes including amnesia, anxiety, hallucinations, and other neuropsychiatric symptoms, but does not list hyperhidrosis as a prominent adverse effect. 1, 4

Potential Mechanisms if Sweating Occurs

While not a typical side effect of orexin inhibitors specifically, if hyperhidrosis develops in a patient taking these medications, consider:

• Orexin system involvement in autonomic regulation: The orexin/hypocretin system plays a role in autonomic nervous system regulation, and blocking orexin receptors could theoretically affect thermoregulatory centers, though this is not well-documented in clinical trials. 6
• Drug-induced autonomic dysfunction: Hyperhidrosis may be caused by drugs acting at the hypothalamus, spinal thermoregulatory centers, and sympathetic ganglia or at the eccrine-neuroeffector junction. 7
• Serotonergic syndrome consideration: If the patient is on concomitant medications (particularly SSRIs or other serotonergic agents), sweating could be part of a mild serotonergic syndrome, which includes headache, nausea, sweating, and dizziness. 6

Management Algorithm

Step 1: Dose Reduction

• Reduce suvorexant to 5-10 mg as the first management strategy, as lower doses maintain efficacy while minimizing adverse effects. 2

Step 2: Environmental Modifications

• Recommend moisture-wicking sleepwear and bedding to manage nighttime sweating. 2
• Keep bedroom temperature cool (65-68°F/18-20°C) to minimize sweating episodes. 2
• Advise avoiding caffeine, alcohol, and spicy foods, which can exacerbate sweating. 2

Step 3: Evaluate Concomitant Medications

• Review all medications for potential drug interactions, especially SSRIs, which may have additive effects on sweating. 6, 2
• Monitor for other signs of serotonergic syndrome if patient is on multiple psychotropic agents. 6

Step 4: Consider Alternative Agents

• If sweating persists despite dose reduction, consider switching to ramelteon (melatonin receptor agonist) which has a different side effect profile. 2
• Low-dose doxepin (3-6 mg) shows strong evidence for sleep maintenance with different adverse effects. 1, 2
• Cognitive behavioral therapy for insomnia (CBT-I) should be considered as first-line non-pharmacological approach. 1, 2

Critical Pitfalls to Avoid

• Do not assume hyperhidrosis is a typical orexin inhibitor side effect without ruling out other causes, including concomitant medications, underlying medical conditions, or environmental factors. 2, 7
• Do not abruptly discontinue the medication without having an alternative insomnia treatment in place, as this may lead to rebound insomnia. 2
• Monitor for dose-dependent increases in somnolence when adjusting doses, as this is the most common adverse effect. 4, 3