Does venlafaxine (Effexor) increase the periodic limb movement index (PLMI)?

Venlafaxine and Periodic Limb Movement Index

Yes, venlafaxine (Effexor) increases the periodic limb movement index (PLMI) and can significantly worsen periodic limb movements during sleep.

Evidence for Venlafaxine's Effect on PLMI

The evidence clearly demonstrates that venlafaxine increases periodic limb movements during sleep:

• A study of normal volunteers showed that venlafaxine administration for just 4 consecutive days induced periodic limb movements at a frequency above 25 per hour in 6 out of 8 participants 1.

• In a larger clinical study comparing different antidepressants, patients taking venlafaxine had significantly higher mean PLMIs compared to control subjects. The odds ratio of having a PLMI greater than 20 was 5.24 for the venlafaxine group compared to controls 2.

• A systematic review examining the influence of antidepressants on restless legs syndrome and periodic limb movements identified venlafaxine as being associated with an increase in both RLS symptoms and periodic limb movements 3.

• Another study documented that venlafaxine decreased sleep continuity (decreased total sleep time and increased wake time) in addition to affecting REM sleep parameters 4.

Mechanism of Action

The mechanism behind venlafaxine-induced PLMS appears to be related to its pharmacological properties:

• Venlafaxine inhibits the reuptake of serotonin, norepinephrine, and to a lesser extent, dopamine 4.

• The increase in PLM is likely due to enhanced serotonergic availability and secondarily decreased dopaminergic effects 2.

Clinical Implications

This finding has important clinical implications:

• For patients with existing sleep disorders: Venlafaxine should be used with caution in patients with pre-existing RLS or PLMD, as it may worsen their condition.

• For patients developing new sleep complaints: Consider PLMD as a potential cause if patients on venlafaxine report sleep disturbances, daytime fatigue, or unrefreshing sleep.

• For monitoring: Patients on venlafaxine who report sleep disturbances may benefit from polysomnography to assess for PLMS.

Management Options

If a patient on venlafaxine develops significant PLMS:

1. Consider alternative antidepressants: Bupropion appears to have a lower risk of inducing PLMS compared to venlafaxine and SSRIs 2.

2. Timing of administration: If venlafaxine must be continued, consider administering it earlier in the day rather than in the evening.

3. Treat the PLMS: For patients who need to remain on venlafaxine but develop troublesome PLMS:

   • Alpha-2-delta ligands (pregabalin or gabapentin) are recommended as first-line treatments for PLMD 5.
   • Consider checking serum ferritin levels, as iron supplementation may help if levels are below 50 ng/mL 5.

Pitfalls and Caveats

• Not all patients on venlafaxine will develop clinically significant PLMS.
• The PLMS may not cause arousals or awakenings in all patients, so some may have elevated PLMI without sleep complaints.
• When evaluating sleep complaints in patients on venlafaxine, consider other potential causes including primary sleep disorders like obstructive sleep apnea.
• Remember that PLMS are considered clinically significant when the PLMS index exceeds 15 per hour in adults 6.

In summary, clinicians should be aware of this association and consider it when prescribing venlafaxine, particularly in patients with existing sleep complaints or those at risk for sleep disorders.