In what clinical scenarios do you utilize opioids in patients with restless leg syndrome?

I would say in refractory RLS, i.e., the patient has failed all the options below:

1. Iron supplementation if ferritin <50,
2. Gabapentin/pregabalin,
3. Dopamine agonists, and
4. Non-pharmacological options (like the vibrating pad).

*I don't love carbidopa/levodopa for RLS. It very often causes augmentation.

Severe treatment-resistant symptoms that remain after trial and adequate titration of gabapentin as well as pregabalin. I have seen better efficacy with pregabalin and the dose may need to be as high as 450 mg. Augmentation of gabapentin/pregabalin with a very low dose dopamine agonist can be considered before transition to opioids. Usually, the cases that require opioids have a strong familial history. When using an opioid, I usually start and have the most success with methadone 5-20 mg. If there is a problem with methadone's duration of action, I usually consider oxycodone before codeine. Tramadol is not effective and should be avoided. Doses of methadone >20 mg are not needed. Extended-release gabapentin, which is FDA approved, can be considered if able to obtain insurance coverage before progression to methadone. Evidence supports opioid therapy, namely methadone, in such cases, and I have had good clinical success with methadone once a patient is transitioned. Opioids may be needed when getting a patient off of high-dose dopamine agonist therapy and then reconsidered once off. High-dose dopamine agonist therapy should be tapered and not suddenly stopped, as acute dopamine withdrawal can lead to suicidality/suicide completion. I am a sleep physician, so I have access to and the ability to ensure that the sleep-disordered breathing status is known and addressed when prescribing opioids for severe RLS. If the patient did not have sleep apnea prior to opioid therapy, I will retest with an in-lab polysomnogram after initiation to ensure that they do not have a new onset of sleep apnea (obstructive and central). The in-lab testing is more accurate and allows for assessment of improvement in leg movements before (RLS) and during sleep (PLMD).

Opiate medication is certainly an option for patients with RLS. Recent guidelines from the AASM (Winkelman et al., PMID 39324694) recommend them, but not as first-line treatment. Due to the side effects, potential for abuse or misuse, as well as stigma of these medications, I use them sparingly and when other options have failed. My first-line treatment is always the gabapentinoids. I will start with these medications, as well as making sure the patient's iron is at the target for RLS. So if these treatments fail, meaning I have repleted iron and reached the target and reached the maximum dose or maximum tolerated dose of gabapentinoids, I will consider an opiate medication for patients who continue to have severe RLS symptoms. The formulation I choose depends on the patient's symptoms. For those who have it in the late evening and/or when attempting sleep, short-acting low-dose opiates like oxycodone have been effective in my experience. For more refractory RLS with symptoms lasting longer, occurring in the afternoon through the evening, and/or waking them from sleep, then I consider longer-acting opiates like methadone. Finally, I have used the lowest dose buprenorphine/naloxone films cut into 1/8ths for patients with severe treatment-refractory RLS with augmentation. In my experience, and in speaking with my colleagues, once a patient with RLS is on an opiate, it is extremely rare to come off of one. Also, in any patient that I start an opiate on, I will repeat a PAP titration if they are already on PAP for sleep disordered breathing (SDB), or if they do not have a diagnosis of SDB, I will obtain a diagnostic PSG to assess for opiate induced central apneas or worsening of obstructive sleep apnea. Finally, I will not use these medications in patients with a history of substance use or abuse, and for anyone with any other contraindications to these medications, obviously. In addition, all patients must sign a medication agreement.