Will I Get Addicted to Opioids from My Restless Legs Syndrome (RLS) Treatment?: Part I; A ReLACSing Blog #31
The concerns about opioids in the treatment of restless legs syndrome (RLS) can be asked many different ways: If I start taking opioids, will I ever be able to stop? Will I get addicted? Will they turn me into a drug addict? Can I become dependent on them? How hard will it be to come off the drug? These are all valid concerns, and they are dependent (pun intended) on many individual factors. In the context of RLS, however, as a unique circumstance in which opioids are used and compared to chronic pain or even recreational use, expert experience and literature evidence point to outcomes for individuals far more favorable than one would imagine. This blog assesses the risks of abuse and dependence with opioid therapy for RLS.
FIrst, before we talk addiction, why are we talking about opioids for RLS in the first place? It may come as a surprise to many clinicians, though not many RLS patients, that opioids are the oldest treatment for RLS, dating back to the 17th century in the days of Sir Thomas Willis. Opioids are also called narcotics and are pain medications that attach to the opioid system in the brain, relieving pain and sensations. In modern times, opioids were found to be extremely effective for RLS and have been used for more severe cases for 3–4 decades now. Methadone is one opioid that seems to be the most commonly prescribed for RLS including some studies on the attributes of those taking methadone for RLS like this one and that one. The largest randomized clinical trial on opioids in RLS was on extended-release oxycodone in Europe a decade ago in which the drug showed a large improvement in those with severe, difficult-to-treat RLS. RLS specialists are well aware that these are the most powerful drugs for RLS, particularly when other first-line treatments are ineffective. Those with RLS also know their effects, particularly if they were coincidentally on an opioid for a short time after the dentist pulled out a tooth or the orthopedist pulled out a knee. Though they were focused on healing from the procedure, if you ask them, they found that their RLS was remarkably improved in those days on the pain killers. The downside of opioids is well known including risk of poisoning and the current opioid epidemic in the US. This is why these medications are not given to everyone with RLS, regardless of how effective they are.
As we turn back to problems with opioids (read this blog post for a summary of all potential downsides), let us talk about medical terminology, which can be confusing. “Addiction” can mean many things and is an imprecise term when used medically. It generally may refer, in medical jargon, to “abuse” or “dependence” or both. There are also several different flavors of dependence as well, not all of which are a negative thing. Recently, the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-V for short), combined abuse and dependence under the umbrella of “Substance Use Disorder,” which is fine but may cause even more confusion when trying to assess this. For the diagnosis of opioid use disorder, one must have two of 11 possible traits for the diagnosis. The details of these are a little complex, but it may make more sense, instead, to talk about abuse and forms of dependence.
Photo by Volodymyr Hryshchenko on Unsplash
One can think of abuse of opioids as using these substances for reasons outside the range of the medical intent. This may be taking them to get high (euphoric effect), taking more than prescribed, craving or obsessing over the next dose, going to great lengths to obtain opioids including those not prescribed or legitimately obtained through a physician and pharmacy, consuming the drug despite recommendations to stop, or using them in the face of physical or social harm. From my experience, the experience of many RLS specialists, and the research published that has examined opioids as RLS medications, abuse is uncommon for those taking low-dose opioids for RLS. Why this may be will be explained later.
The term dependence is now a component of opioid use disorder and not considered an independent entity, but I like to consider the concept of dependence on its own and as having three domains: medical, psychological, and chemical. Medical dependence means that one is dependent on the drug for its medical benefit. Though it is great to have options and flexibility, medical dependence in some ways is a good thing because it also means that an individual may have found a treatment that works. In the absence of the drug, the condition would be poorly controlled or there are few options otherwise to keep the symptoms at bay. Medical dependence on opioids is very common in those taking them for RLS. This is often the case because once an individual gets to the point that they require opioid therapy, it means they have been unsuccessful with several other treatments and have a moderate or severe degree of the condition. As mentioned above, opioids are generally very effective and may be the only remaining treatment option for the condition. In other words, they are effective when everything else is not, and they work. You take them away, the situation may not be good. Due to the dopamine agonist crisis from continued widespread prescribing over the past two decades, there are thousands of those with RLS suffering from augmentation who may require opioids. Consensus first-line approaches such as lifestyle, sleep, and other behavioral interventions, iron supplementation and infusion, and the class of alpha-2-delta ligands (aka the gabapentinoids) are often ineffective in the face of augmentation. This leaves opioids as the main option for many. Fortunately, they are highly effective and well-tolerated in most people, but this leads to a medical dependence in that this is the only option, and if taken away, the RLS may be quite severe.
As an example, Philbert has been on 5 mg of oxycodone close to bedtime for RLS after several treatment failures. He is admitted to the hospital for hip replacement surgery. His hospitalist physician has been focused on arranging physical therapy as well as his blood pressure and cholesterol medications and forgot to order oxycodone for RLS. Later that night Philbert develops severe RLS without the oxycodone, not mention with his hip immobilized. The overnight physician assistant on call tells him that they do not prescribe opioids after hip surgery and use alternative treatments. He does not believe that Philbert needs opioids for RLS and suspects he is using it as an excuse to get pain medications. Philbert struggles throughout the night without his medication and barely sleeps. Five milligrams of oxycodone is not enough to cause a chemical dependence. Philbert is not abusing oxycodone and does not have opioid use disorder. Philbert is medically dependent on oxycodone to relieve his symptoms of RLS.
I would describe psychological dependence as a situation in which one perceives the need to take an opioid whether or not one actually needs it. There may be emotional distress related to the thought of not having the medication or lowering the amount taken. There could be anxiety over what may happen if the medication is no longer there, and it may be based on previous experiences. The medical dependence (see above) and chemical dependence (see below) can of course lead to a well-founded fear of what will happen without the drug. However, it could also be the apprehension from previous, uncomfortable experiences, which may not reflect the present.
Let’s use the classic case of Martha as an example. Martha has long standing RLS, surviving previous augmentation from ropinirole several years ago. She has been doing well on methadone at 7.5 mg every evening. This past year, she was found to be extremely iron deficient and obtained an intravenous (IV) infusion of iron of 1000 mg. Two months later, she has not had any RLS symptoms for three weeks. Her physician, let’s call him something completely random like Dr. Berkowitz, suggests that she may be long recovered from augmentation and is no longer iron deficient. Could she try to decrease methadone to 5 mg? Martha thinks back to when she was on ropinirole and what happened if she missed her second dose at bedtime. She is worried that her RLS will come back with a vengeance. Sure, Martha may be medically dependent on methadone, but the question is what will happen if she decreases the dose by 33%? Would it really be intolerable? Is it possible that the worst case would be that the condition is a little bothersome for a week and then Dr. Berkowitz increases it higher to 6 mg? Is there a chance that the condition has improved and she would be fine now on the lower dose? The psychological dependence here could be a barrier, and this can be common in opioid treatment with RLS. It certainly makes it more challenging to answer affirmatively to the question of whether one will ever “get off the opioid.”
The most well known form of dependence is chemical dependence. Common substances that can cause chemical dependence include caffeine, nicotine, and alcohol. This can be seen in prescription drugs like benzodiazepines (e.g. clonazepam), opioids, amphetamines (e.g. Adderall®) and, most likely, dopamine agonists as well (though not yet completely understood). If one takes a chemical for long enough, on a daily basis, and at a high enough strength, the brain adapts to the drug and essentially gets used to having it around. The brain can no longer function at its baseline without the drug present. If the drug is suddenly gone, the brain stops working well and there may be withdrawal effects.
As an analogy, Jack used to climb six flights of stairs in the parking structure at his workplace to reach his assigned parking area. The company puts in a swanky new elevator with neon lights and Muzak, and Jack starts using it. One day, the elevator breaks down, and he has to climb six flights of stairs to get to his vehicle. He huffs and puffs all the way up with his heart racing. The next day, Jack wakes up with sore thighs and achy calves. Jack is chemically dependent on that elevator. Those irritated muscles and poor exercise tolerance are the withdrawal symptoms. Not the best analogy. At least I didn’t say that Jack was climbing up the hill to fetch a pail of water, but fortunately, aside from some muscle soreness, he did not break his crown in the stairwell…
The risks of chemical dependence with opioids and RLS is possible but less common than in those taking opioids for chronic pain and certainly less than those using opioids recreationally. For those with RLS that do have chemical dependence, it may not necessarily be a huge problem. It is possible that those who are chemically dependent (but not medically dependent) could taper off opioids over the course of several days or weeks without any adverse effects if done under medical supervision. This can be far smoother than many other classes of drugs including benzodiazepines (sedative-hypnotics) and certainly dopamine agonists.
Felicity has been taking 300 mcg of the buprenorphine buccal film and needs to have her gallbladder removed as an elective surgery in a few weeks. Her surgeon is unfamiliar with this drug and requests that her RLS doctor—let’s refer to him as Dr. Burke—get her off the buprenorphine prior to surgery. Dr. Burke prescribes the 75 mcg films and advises Felicity to taper buprenorphine films by 75 mcg every three nights until she is off prior to surgery. Felicity is gradually put on pregabalin (Lyrica®) over the same time to relieve her RLS symptoms. She had been on pregabalin in the past for RLS, which was effective, but wanted to go off due to weight gain on the medication. She is ok with using pregabalin for a few weeks. Felicity follows Dr. Burke’s cross-titration instructions and experiences no opioid withdrawal symptoms.
Granted that in this case, 300 mcg of buprenorphine is not likely to cause chemical dependence in the first place, but just imagine that she could be dependent on it chemically. Here she is able to taper smoothly off the drug and maintain her hopes of having that gallbladder out. She is not medically or psychologically dependent here because she knows the pregabalin will work in the short term even if it is not the best for long-term use in her case.
The last term to define is tolerance. Tolerance is related to chemical dependence in that as the brain gets used to having the medication around, it fails to perform even its baseline functions at the current amount of medication and needs even more of the drug to run effectively. The brain reorganizes itself to accommodate the drug effect but over time, it goes too far and the functions that it performed along with the drug are now performed even to a lesser extent.
Sven is a college student taking a class on late 19th century government regulation of the train industry, which happens to be at 1 pm. Despite the enthralling topic, he struggles to maintain alertness particularly at the low point of his circadian rhythm after lunchtime. He begins drinking one espresso shot prior to class with lunch, but it perks him up so consistently for class that he drinks the espresso every day. Halfway through the semester, he cannot stay awake during class any more and needs a latte with an espresso shot, which now succeeds in waking him up. He also notices that he has headaches in the afternoon if he forgets to have the espresso. Sven is now chemically dependent on the caffeine from the espresso, as evidenced by the withdrawal headaches when he misses his swig. Moreover, he exhibits caffeine tolerance because the previous amount of caffeine from the espresso no longer can keep him awake and he needs more.
We see this commonly with dopamine agonists for RLS. Pramipexole works at 0.25 mg for two years and then suddenly symptoms are breaking through at night. “The condition is getting worse,” says the unsuspecting doctor, who sends in an e-prescription for the 0.5 mg tablets. The new dose is effective, but only for another six months…Tolerance from dopamine agonists is now thought to be part of the spectrum of augmentation development. If a lower dose worked for a length of time and now a higher dose is required to relieve RLS symptoms like before, this can be considered a symptom of augmentation, particularly if no other trigger like low iron or new RLS-triggering medication is the cause of the RLS getting worse. For opioids, tolerance is uncommon in RLS treatment, less so than seen in those with chronic pain. However, it is still a potential risk.
Now that the groundwork has been set defining the terms addiction, abuse, dependence, tolerance, and opioid use disorder in the context of RLS, let us pause for this week. Next week, Part II will shine a light on the research that shows why these situations are much less concerning in reality than as currently perceived by the mainstream medical community. We will then conclude with what has been done to limit further the already lower risks of these essential medications for those suffering with RLS.
For those who cannot–ahem–tolerate the wait for the next blog, feel free to view the full summary in high def at the @andyberkowskimd YouTube channel.
-Andy Berkowski, MD of ReLACS Health, psychologically dependent on verbosity in blog posts
