10 of the Most Common Side Effects of Opioids for Restless Legs Syndrome (RLS): A ReLACSing Blog #28
For over a quarter century now, since the first use of carbidopa-levodopa (Sinemet®) in the 1990s and then with the inundation of dopamine agonist prescriptions at the turn of the century (1) including pramipexole (Mirapex®), ropinirole (Requip®), and transdermal rotigotine (Neupro® patch), clinicians that treat restless legs syndrome (RLS) have seen an unprecedented level of severity of RLS. This is due to the phenomenon of augmentation, which is a medication-induced and artificial worsening of the condition with long-term use of dopamine agonists. Now, in the present century more than ever, stronger treatment options are needed to combat the wave of severe RLS seen in the clinic. However, doctors that are knowledgeable about RLS must come crawling back to an old, maligned pal–the opioid. These have been used since the days of Sir Thomas Willis, well before the turns of four centuries ago in the 1600s. The oldest described treatment for RLS remains the most powerful to fight the plague of augmentation that will ravage the field until word reaches the front-line clinicians, whether by horse-drawn messenger or telegram or facsimile–or whatever technology that has led to delays in the dissemination of medical information–that doctors should rarely ever reach for their prescription pad to put an inked quill to papyrus for a dopamine agonist. Despite being a powerful older treatment, opioids too have their risks, side effects, and downsides, so this blog attempts to summarize some of the ten main side effects of opioid therapy for which to look out if these are required for the treatment of RLS.
Photo by Ksenia Yakovleva on Unsplash
Before we go into the ten side effects, let us review why one with RLS would want to be exposed to opioid treatment and the forthcoming side effects for RLS in the first place. Opioids are a consensus treatment for moderate to severe RLS when the first-line approaches have failed to be effective. In general, RLS treatment should first involve optimization of lifestyle factors and sleep. These can include eliminating vices: alcohol, caffeine, nicotine, over-the-counter sleep aids, etc. Sleep factors can involve maintaining a consistent sleep schedule with a religious wake up time or addressing other sleep conditions like obstructive sleep apnea that can worsen sleep quality or RLS indirectly by causing inflammation. Once these measures are modified, medications that exacerbate RLS can be adjusted or eliminated under clinician guidance, such as the “anti- drugs”: older generation antihistamines, anti-nausea medications, antidepressants, and antipsychotics used for mood or even sleep itself. Iron levels should be assessed in all with RLS who have symptoms significant enough to discuss with a doctor or warrant treatment. Iron levels should be aggressively increased, including potentially through an IV infusion depending on the situation. If medications are required, alpha-2-delta ligands (seizure/nerve pain medications) like gabapentin, pregabalin (Lyrica®), and gabapentin enacarbil (Horizant®) are the consensus first-line medications. If all of these measures have been addressed, and there are still moderate or severe RLS symptoms, or augmentation, opioids are generally considered the next step, regardless of the medical cultural backlash against them in the wake of the opioid crisis in the US. This may be the next best option for some, and here are the side effects to watch out for:
Respiratory depression: respiratory depression is not about feeling down about your lungs or breathing. It is that the ability of the brain to control breathing becomes impaired, or in the worst case, ceases altogether. Respiratory depression can occur in high enough doses from most opioids, with the biggest exception being buprenorphine, which has unique opioid properties that mostly mitigate this risk. The centers of the brain in the brainstem that control breathing can become ineffective at regulating breathing and one can begin to breathe shallow, more slowly, erratically, or not at all. This is the means by which the tens of thousands of opioid-related poisonings occur each year in the US. To a lesser severity, opioids can, in certain individuals, cause a reduced ability to breathe during sleep, called hypoventilation, as breathing is exclusively controlled by the brain and not the conscious mind when sleeping. Hypoventilation can cause low oxygen levels and/or increased carbon dioxide leading to side effects and stress to the heart and cardiovascular system. Central sleep apnea or long pauses in breathing can occur as well. These sleep-related breathing issues are more likely to happen in those with the following factors: significant obesity, untreated obstructive sleep apnea, lung or respiratory problems like COPD, taking other medications at the same time including the above mentioned alpha-2-delta ligands, benzodiazepines, sedative-hypnotic drugs including sleeping pills, muscle relaxants, alcohol, and other chemicals that impair breathing. Most patients taking low-dose opioids for RLS will not encounter breathing issues at all for RLS, but downing the entire bottle or mixing opioids with a batch of the factors listed above can be a concern even in RLS. Anything that can lead to the phrase on the bottle, “may result in impairment, coma, and death” is a pretty big risk. Conversely, downing a bottle of acetaminophen (Tylenol®) can lead to the same result, and that is over-the-counter, so every drug, when used appropriately, can certainly be administered safely.
Abuse: Opioids can be abused. Some are concerned about “addiction,” but this is not really the precise medical term and can connote other medical terms including #3 below (dependence) so I won’t use the term addiction here. When I say abuse, I am referring to using the drug for purposes outside the original intent of the medication as given by the prescriber. This can include chasing the euphoric effect of the drug, aka “getting high,” instead of just taking the prescribed dose to relieve the urge to move from RLS. Often those who abuse drugs will take more than prescribed or in a way that was not prescribed, generally with increasing amounts of the drug. Based on a few decades of consistent use for RLS, along with new findings in the National RLS Opioid Registry including this most recent publication, it does not appear that abuse is very common for those taking RLS in particular, where it could happen more in those of other demographics and for other conditions. It does not mean that there is no risk, but probably less than feared by the medical community and patients themselves. There are ways to mitigate risk by assessing risk factors for opioid abuse including administration of the Opioid Risk Tool by a clinician. It is often thought that an individual’s personality, social environment, mental state, family background, medical situation, and other factors play the most important role in drug abuse, more so than even the drugs themselves. Buprenorphine, followed by methadone, are long-acting opioids commonly used for RLS that are less likely to lead to abuse than other opioids so selection of the specific opioid can be a factor when looking at all the risks as a whole. There are also safeguards in place to detect any aberrant behavior such as opioid agreements, urine drug screens, and mandatory pharmacy database reviews. From my personal experience treating probably a few hundred RLS patients with opioids, the risk of abuse is very low. Otherwise, one would expect to see opioid contracts broken, urine drug screens showing the wrong drugs, or the pharmacy database revealing multiple prescriptions from different providers. I just have not encountered this much, and not for lack of surveillance or turning a blind eye.
Dependence: dependence is sometimes confused with addiction, which again is an inexact word. Dependence can be considered a chemical adaptation of the body or brain to a substance, and if one were to stop the substance, the body would go through withdrawal symptoms. The body is reliant on the substance to continue day-to-day activities at baseline. This sometimes can occur with opioids, particularly at higher doses, but probably less commonly for RLS due to the use of much lower doses than for chronic pain, for example. Opioid withdrawal can be very very unpleasant but fortunately is usually not life-threatening. How does sweating, diarrhea, chills, muscle aches, watery eyes, anxiety, agitation, and yawning sound? Fun fact: RLS itself can be a symptom of opioid withdrawal, even in those who generally do not have RLS. Yes, these symptoms are unpleasant, but alcohol withdrawal can lead to death in many cases; opioid withdrawal should not. If one needed to go off opioids for a particular reason, they could be tapered off over days or a few weeks without any withdrawal symptoms. The one caveat for RLS patients is that there needs to be another treatment for the RLS in place or the symptoms will no longer be controlled. Again, buprenorphine causes significantly less dependence than standard opioids due to the unique way in which it works and can be a consideration for those concerned about dependence or who have become dependent on another opioid already.
Impairment/dizziness: opioids can affect the brain function and cause disorientation, impairment, unsteady walking, falls, dizziness, etc. These side effects can occur if the dose is too strong at the beginning or if the dose is increased by too much. Many people adapt to these effects quickly, sometimes over days, but others can have these effects for many days or weeks and may have to use a lower dose or different type of opioid that is not as potent. Combining opioids with other sedative medications, some of which were mentioned above, can lead to further impairment. Those starting on opioids must be cautious with driving or using heavy machinery until they are confident they are within full coordination to perform these tasks. The combination of opioids with alcohol warrants significant caution for impairment as well.
Nausea and itching: these are some of the minor symptoms that can occur initially and go away after a few days. These can also be variable in the severity, and if they do not go away, they sometimes can be enough to cause a person to stop using the medication. When initiating opioids, it may be best to try to adapt to these side effects naturally. Anti-nausea medications, as mentioned above, actually trigger RLS in most cases so are probably not the best option. Opioids can sometimes cause itching, and unfortunately, the scientific community has a poor understanding of how this occurs. It may not have anything to do with histamine, which is often a cause of itching, such as with that pesky mosquito bite. Older generation antihistamines like diphenhydramine (e.g. Benadryl®)…you guessed it…worsen RLS, so it is probably best to avoid them. Newer generation antihistamines that do not penetrate the brain like fexofenadine (Allegra®) or loratadine (Claritin®), for example, typically do not trigger RLS and may or may not work of itching related to opioids but could be a short-term option to try. Waiting it out and hoping the body adapts could be an option, but how long to wait? For most who may have these symptoms, they resolve within a few days.
Constipation: this is less likely to cause one to stop taking opioids but probably one of the most common side effect complaints. Opioids slow the bowels down by impairing the nervous system that regulates movement of food/stool through the GI tract. Increasing fibrous material (like leafy greens [2] for example) along with lots of water is a good first step. Bulk-forming stool softeners like psyllium husk (Metamucil®) or methylcellulose (Citrucel®) taken daily with water can help the slowed GI system move softer, bulkier stool through more efficiently. Polyethylene glycol (Miralax®) is an “osmotic” stool softener that can also be used effectively as well. Rarely, laxatives that stimulate the bowels are needed, but these should not be used regularly. Even rarer are newer medications designed to reverse constipation from opioids directly, which can include naloxegol (Movantik®), again, not typically needed at the opioid levels used for RLS but definitely available.
Depression: in addition to respiratory depression, there is an increase in mood depression, or major depressive disorder symptoms, with long-term use of opioids. In some cases, this could be an association with opioids but not caused by opioids. For example, many people with depression have worsened pain conditions, which may lead to more opioid use, but they may not have had depression due to the opioid use as the original cause. Similarly in RLS, there are some factors indicating increased depression with RLS and more severe cases of RLS. More severe RLS leads to increased likelihood of needing opioids. Dr. John Winkelman’s group at Mass General recently published an abstract of the RLS Opioid Registry showing an increase in suicidal thoughts in those with severe RLS on opioids. This was less the case on methadone over other opioids. It was unclear whether this could be due to the anti-NMDA effects of methadone or the fact that methadone could have led to better RLS control, and thus less depressive symptoms. Dopamine agonist withdrawal and recovery from augmentation can lead to depressive symptoms as well, and those trying to come off dopamine agonists often need treatment with opioids. The bottom line is that depressive symptoms need close monitoring when patients are on opioids long term.
Low testosterone and other hormonal effects: occasionally, long-term use of opioids can lead to lower testosterone levels or effects on other hormones. Opioids may lower the function of some of the hormone centers of the brain including the hypothalamus and pituitary gland as well as the testes and ovaries themselves. Loss of energy, reduced sex drive/libido, sexual dysfunction, changes to menstrual cycles in women, and other sex hormone related symptoms can pop up. These issues do not often come up but should be mentioned to the prescribing clinician; sometimes they can be addressed with simple lab testing by the primary care physician or referral to a hormone specialist like an endocrinologist or gynecologist/urologist.
Dental problems from buprenorphine: As mentioned in this video, the FDA released a notice about forms of buprenorphine taken by mouth (including Suboxone® that dissolves under the tongue and Belbuca® that is absorbed between the cheek and gum) being associated with an increased risk of dental problems including cavities, infections, and tooth decay. The risk is close to 2% in this study of those taking buprenorphine for opioid use disorder, though this is a demographically different population from those taking it for RLS. Nevertheless, this is something to be aware of. One should rinse their mouth out with water after buprenorphine dissolves to help lower the acidity in the mouth that is theorized to cause the problems. One should not brush teeth immediately after taking the medication when the teeth are more vulnerable to the friction of the toothbrush. However, those taking buprenorphine should maintain excellent dental hygiene with regular brushing and flossing otherwise. One should see the dentist regularly and make them aware of this increased risk with the buprenorphine preparations taken by mouth.
Heart conduction problems from methadone: methadone can have a slight effect on heart conduction, though more at doses much higher than taken for RLS. Something that shows up on an electrocardiogram (ECG/EKG) is a time measurement called the QT interval, and this can be increased with methadone. It can also be increased with other heart conditions, heart medications, and electrolyte imbalance such as low potassium or magnesium. It also could be affected by other types of medications like certain antibiotics and many of the aforementioned “anti-drugs” like tricyclic and SSRI antidepressants, anti-nausea medications, and antipsychotics. This is why clinicians want to be aware of all medications and supplements one is taking as well as other health conditions like heart problems when prescribing a new medication. If one is on methadone already and is suddenly prescribed a Z-pak for pneumonia, that antibiotic could affect the QT interval. The doctor prescribing the antibiotic should be aware that the individual is on methadone. In some cases, particularly in the elderly, those with heart problems, or those with other medications that can affect heart conduction, an ECG should be performed prior to and after starting methadone for RLS. A serious heart arrhythmia can occur if a bad combination of these situations lengthens that QT interval too much, so being aware of this risk beforehand for prevention is important.
Though buprenorphine and methadone have become two of the most commonly prescribed opioids for RLS, it is important to note that each medication in this class may have its own risks and benefits, but hopefully this covers ten of the most common and important. Also, this blog is intended to increase awareness and education, not to scare off those suffering with RLS to use opioids! Taking opioids may be a better choice than continuing to deal with miserable RLS when other approaches have failed. RLS already is climbing uphill against the avalanche against the anti-opioid prescribing medical environment, so patients refusing to take opioids due to side effects should not be another barrier to appropriate RLS treatment. As I always mention, for every treatment there is probably a positive effect and negative or side effect. One must select a treatment–or choose no treatment at all–by weighing the beneficial effects with the true potential adverse effects (whether perceived or real). In some cases, opioids are the right choice, but one should always be aware of the side effects.
-Andy Berkowski, MD of ReLACS Health, who hopes to prescribe increasingly less opioid treatment in future years as more and more RLS patients eschew dopamine agonists and get more iron infusions
(1) Don’t make yourself feel old. The turn of the century means the 21st century! It sounds more eloquent than “the aughts.”
(2) Spinach is a leafy green that is among the highest in iron among vegetables, so this could be a great double-whammy, just ask Popeye (not the fast food chain, but the sailor man)
