Tramadol is an opioid painkiller similar to morphine, although it is much weaker. Aside from interactions with the opioid system, it also directly produces effects in the serotonin and norepinephrine neurotransmitter systems which is unique among opioids. Serotonin is a mood elevator, regulator, and aids digestive function while norepinephrine is responsible for attention, learning, and affects emotional states. As far as it’s opioid interactions are concerned, tramadol is roughly 5 to 10 times weaker than morphine milligram-per-milligram depending on the route of administration. The opioid interactions, while frequently being weaker than with other opioids, are amplified by the effects produced in serotonin and norepinephrine systems.
When someone uses tramadol, it will weakly bind with the μ-opioid receptor while also acting as a reuptake inhibitor of serotonin and norepinephrine. This acts to increase levels of serotonin and norepinephrine in between neurons, leading to stronger signaling produced in these symptoms. The opioid stimulation combined with the increased signaling in these other neurotransmitter systems can combine to produce a greater analgesic effect than would be achieved through μ-opioid stimulation alone.
Using tramadol for an extended period, usually just a few weeks of daily use, the brain will begin to adapt to its presence. The chronic stimulation to μ-opioid receptors will cause the brain to reduce the sensitivity of these receptors in an attempt to maintain balance through a process called downregulation. This will also occur with serotonin and norepinephrine systems, as continued reuptake inhibition leads to elevated signaling in these systems. After downregulation has begun, a further and more comprehensive process known as the neurological remodeling will begin. Remodeling is the process of enacting structural changes that will allow the brain to operate more efficiently in a μ-opioid, serotonin, and norepinephrine downregulated environment. While downregulation may happen fairly quickly, remodeling is a slow process that often takes months to produce noticeable changes. 1, 2, 3, 4, 5, 6, 7
Once downregulation has occurred, someone will begin to feel physically and psychologically unwell when they go too long without using tramadol. The symptoms of tramadol withdrawal manifest as physical and psychological symptoms in the short term, known as acute withdrawal, and longer-lasting psychological symptoms, known as post-acute withdrawal, that may last for months or even years. As with most opioids withdrawal syndromes, there is a fairly clear distinction and timeline progression for these two phases.
The symptoms of tramadol withdrawal will include the physical symptoms of withdrawal from other opioids, although there may be more psychological unrest than with other opioids. Even though tramadol may not be as potent as many other opioids, the additional interactions with serotonin and norepinephrine systems can cause more intense psychological symptoms and these may persist for longer as well.
Some of the symptoms of tramadol withdrawal include:
Tramadol withdrawal symptoms are not usually dangerous themselves, but if someone has a pre-existing health condition they may be at an increased risk for dangerous complications. People who have co-occurring heart health issues or diabetes are at an increased risk for cardiac arrest, although this is very rare, and diabetic ketoacidosis or hyperosmolar hyperglycemic nonketotic syndrome (HHNS), respectively. Additionally, older people who use tramadol and who are suffering from osteoarthritis are at an increased risk of potentially fatal outcomes, although the mechanism for this is unclear. This may be due to either tramadol use or tramadol withdrawal and further research is needed to discern the exact causes, risks, and some possible preventative measures. 10, 11, 12
While the post-acute symptoms of tramadol withdrawal may be strictly psychological, they can still pose dangers and challenges to someone’s continued recovery. Additionally, the sometimes profound depression that can arise during withdrawal can lead to suicidal thoughts, and unfortunately, suicide attempts. While these risks are indirect, they can result in very unfortunate outcomes and should not be taken lightly. Finally, these symptoms can be quite long-lasting, oftentimes persisting for months or even years in some cases.
Some of the most common post-acute symptoms of tramadol withdrawal include:
These symptoms may be most intense in the days, weeks, and months immediately after ceasing tramadol use and usually dissipate over time. While the physical symptoms are due to downregulation, the prolonged post-acute symptoms are due to the neurological remodeling that occurs after downregulation has begun. While these symptoms may not seem severe, they can pose a serious hurdle to someone’s continued sobriety. Aside from depression and anxiety promoting isolationist behaviors, the cravings for tramadol can sometimes grow more intense over the first few months. As the memory of the pain and discomfort of withdrawal fades, the idea of a return to tramadol use may seem more and more attractive. If someone has not done so already, it is highly recommended that they seek out treatment and care as soon as possible as having support, care, and direction during this time can be crucial.
The timeline for tramadol withdrawal symptoms is fairly standard in most people. That being said, genetic factors can increase or decrease this timeline, sometimes substantially, but we will discuss this more a little later. In general, the timeline will exhibit fairly standard opioid withdrawal appearance, plateau, and resolution although there may be slightly more gastrointestinal upset and psychological symptoms than with most other opioids.
Tramadol has an intermediate half-life of around 6 hours in healthy adults and combined with its fairly weak μ-opioid receptor interactions, the physical withdrawal symptoms may not reach severe levels. Withdrawal symptoms often begin within 8 to 10 hours of the last drug use and will escalate, stabilize, then resolve over about 7 days. This first week will exhibit the worst of the physical symptoms, and the psychological symptoms can be quite severe during this time as well. 1, 13
Here, we will take a look at the symptoms of tramadol withdrawal on a week-by-week basis:
Within half a day from the last tramadol use, withdrawal symptoms will begin to appear. The first symptoms are usually sweating, increased anxiety, and minor chills. Over the next 24 hours, these symptoms will intensify and are often joined by hot flashes, a very runny nose, stomach pains, cravings for tramadol, restlessness, fatigue, and tremors. The second day frequently exhibits pains in the muscles, joints, and bones, alongside other symptoms such as increased heart rate, elevated blood pressure, insomnia, loss of appetite, vomiting, diarrhea, and allodynia. These symptoms will often worsen over the first three or four days before reaching a plateau. They may remain at a fairly stable level for a day or two before beginning a resolution over the next few days. A common timeline for the worst of the physical symptoms is between five to seven days, depending on someone’s use habits.
The beginning of the second week often proves much better than the beginning of the first week. The physical symptoms are usually well on their way to total resolution by now, with the exception of sweating and diarrhea. The psychological symptoms, while usually staying fairly stable during the first few weeks, may be more pronounced during this time as the physical symptoms are no longer as distracting. This may make it seem like they have gotten worse, as someone is more acutely aware of the mental discomfort during the second week. Insomnia may still be present as well, although it is often much improved. Once appetite begins to return to normal and someone begins eating more food and more regularly, this can also go a long way towards improving someone’s subjective experience of tramadol withdrawal symptoms.
By the third week, the physical symptoms are usually totally resolved. Insomnia may still be somewhat problematic, although this is usually more psychological in nature rather than physical. Depression, anxiety, and cravings are frequently still present at fairly high levels and mood swings may be expected as well. As the memory of withdrawal fades over time, it is not uncommon for someone to reminisce and think about tramadol use fondly. This time is very critical, as most opioid relapses happen during, or shortly after acute withdrawal.
After four weeks since the last tramadol use, often the only remaining symptoms are psychological in nature. Sleep has usually returned to normal, and appetite levels or stomach issues are often resolved by now. Depression, cravings, and anxiety are almost certainly still present and may be for some time still. If someone has not already entered treatment after detox, it is highly recommended that they do so now. The risk of relapse is real, and the cravings for tramadol can come and go. It is not uncommon to experience no cravings for weeks or months, only to have them appear suddenly and strongly. Continued care and treatment can provide the tools needed to deal with the cravings and other psychological symptoms in a healthy, sober way.
While the symptoms of tramadol withdrawal are rarely fatal, they are almost always extremely uncomfortable. Entering a tramadol detox center can help reduce the discomfort and the risks of withdrawal through medications and medical monitoring. Furthermore, they can provide behavioral and clinical therapy to help someone find relief from the psychological symptoms and develop new, healthy ways to cope with tramadol withdrawal and life after detox. Entering one of these facilities can also provide connections and resources for continuing recovery and care after detox has been completed. This can make the difference between someone achieving a healthy and long-lasting recovery or relapsing back into tramadol use.Tramadol Detox Centers
The physical effects of tramadol withdrawal, while rarely dangerous on their own, can be quite uncomfortable. The downregulation that occurs to μ-opioid, serotonin, and norepinephrine receptors can result in disruptions to a variety of physical systems and processes. While all of these neurotransmitter systems are involved in cognition and psychological processes, they are also important in several vital systems as well, either directly or indirectly. Here we will look at some of the effects of tramadol withdrawal on a system-by-system basis.
Serotonin is extremely important for mood and mood regulation, but it is also a critical neurotransmitter involved in healthy gastrointestinal function and digestion. Around 95% of all the serotonin in the body is located in the gastrointestinal tract, and here it works to regulate and moderate intestinal muscle contractions among other things. In addition to serotonin, opioid receptors have a large impact on the gastrointestinal tract as well. The μ-opioid receptors, in particular, play a very large role in intestinal muscle contractions, stomach emptying into the intestines, and bile production. Due to downregulation in both serotonin and μ-opioid receptors through tramadol use, when someone stops using the drug there can be profound gastrointestinal distress. While serotonin may have an impact, the greatest contributor to the gastrointestinal effects of tramadol withdrawal is μ-opioid receptor downregulation.
Some of the most common gastrointestinal effects of tramadol withdrawal that are directly related to disruptions in these two neurotransmitter systems include diarrhea, stomach or bowel cramps, and a lack of appetite. Some other effects that may be due more to anxiety and norepinephrine increase include lack of appetite and vomiting. These gastrointestinal effects may not seem severe, but they can easily lead to complications, especially if someone has co-occurring health conditions. Diarrhea and the constant sweating that is common during tramadol withdrawal can lead to dehydration, which may increase the risk of dangerous complications, especially in those who have heart conditions or diabetes. 14, 15, 16, 17
Another interesting role of the opioid system is in heart function. This includes effects on the brain’s signals to the heart as well as affecting the heart muscles themselves. While the exact role of μ-opioid receptors regarding heart function, it is known that opioid agonist drugs slow the heart and can reduce blood pressure. This may be a direct effect, or it could be a secondary effect of opioid receptor stimulation reducing stress responses and hormones. In addition, the stress of all of the other symptoms, especially anxiety, can work to increase stress hormones during tramadol withdrawal, so the reduced ability of the opioid system to moderate these stress responses can lead to a cardiovascular overreaction until upregulation can somewhat restore proper neurotransmitter function and balance.
Another neurotransmitter that is affected by both tramadol use and withdrawal is norepinephrine. This acts as both a neurotransmitter when found in the brain and a hormone when found in the blood. While in the brain it acts to promote attention, learning, and emotional regulation, in the blood it acts as a hormone and a mediator of the release of another hormone, epinephrine (aka adrenaline). Norepinephrine levels are increased during opioid withdrawal in general, and the additional effects that tramadol produces may complicate this process further. Increased norepinephrine levels can lead to increased heart rate, elevated blood pressure, and increased blood sugar levels. This may not be dangerous for most people, but again, if someone had prior heart health issues or diabetes, they could suffer severe consequences if they do not receive medical attention during tramadol withdrawal. 18, 19, 20, 21, 22
While these two major systems experience physical effects, there are a variety of other processes or systems that are disrupted as well. Some of the secondary effects of tramadol withdrawal are less noticeable and are almost never dangerous. These include internal and external effects in a range of other physical systems.
Some of the most common effects of tramadol withdrawal due to increased levels of norepinephrine include:
Some common effects due to general autonomic nervous system disruption include:
Another common effect with no known cause is:
While the physical effects may present the most immediate and obvious risks, the psychological effects of tramadol withdrawal can introduce risks of their own. These effects can be simultaneously hyperactive in the form of cravings and anxiety and depressive in the form of depression, possibly with thoughts of suicide. The mental discomfort that often arises during withdrawal can act as a barrier to someone being proactive in their recovery. The state of mind that often accompanies withdrawal can cause someone to isolate and be fearful of others, making reaching out for further help very difficult.
While depression is a common withdrawal symptom from any opioid, it may be more intense during tramadol withdrawal. This is due to the exact way tramadol works; specifically its interactions with the serotonin system. Serotonin is very influential in someone’s state of mind and mood, with many common and effective antidepressants such as selective serotonin reuptake inhibitors (SSRIs) leveraging this ability to improve mood and reduce depression. When the brain undergoes serotonin downregulation in response to chronic tramadol use and subsequent withdrawal from tramadol, the brain’s normal levels of serotonin will have a reduced ability to stimulate serotonin receptors. This has the effect of lowering serotonin’s impact in the brain which commonly leads to depression, sometimes profoundly so. This is comparable, although maybe not quite as intense, as when someone suddenly stops taking an SSRI antidepressant.
Even after downregulation, the further process of remodeling can also influence these depressive effects. The structural changes that occur in the presence of heightened levels of serotonin due to tramadol use can make it even more difficult for the brain’s natural levels of serotonin to impact the brain as they should. This neurological remodeling process is reversible, but this can take quite a long time. This state of depression can often last months or sometimes even years before the brain is able to return to pre-tramadol levels of function. Medications and therapy can help, but the most effective solution is continued abstinence from tramadol or other drug use. 23, 24, 25
Another very common effect of tramadol withdrawal, anxiety can be very disruptive to someone’s recovery. While baseline anxiety is often heightened, social anxiety is also prevalent during tramadol withdrawal. The exact causes are not fully clear, but it most likely has several sources, both neurological and behavioral. From a neurological standpoint, the opioid system helps regulate levels of anxiety by calming downstream excitatory nerve signals. Additionally, norepinephrine is strongly correlated with levels of anxiety, and the increased levels of norepinephrine during tramadol withdrawal can also contribute to the symptoms of anxiety.
From a behavioral standpoint, tramadol use can become an extremely powerful, albeit unhealthy, coping mechanism. Someone using tramadol may begin to use it for a sense of relief from the normal stresses of life. As use increases, so does reliance on the drug for a sense of security and peace. When this is suddenly removed, someone can feel helpless and hopeless, and this can cause severe anxiety. Medications and therapy can help treat the symptoms of anxiety, and developing new and healthy coping skills can help reduce the anxiety itself. 24, 25, 26
A very common effect of any opioid withdrawal, cravings can be quite strong during withdrawal from tramadol in particular. Even though tramadol is a painkiller and depressant, it can counterintuitively increase levels of dopamine, a powerful excitatory neurotransmitter, in certain areas of the brain. In particular, the limbic system sees greatly increased levels of dopamine during tramadol use. The limbic system is a major reward center of the brain that is responsible for feelings of pleasure, reward, and is a center for incentivized motivation. The sharp increase in dopamine that results from tramadol use is responsible for euphoria, feelings of pleasure, and behavioral reinforcement to use more tramadol.
Due to the chronic increases in dopamine in the limbic system, dopamine may become downregulated as well. More so than downregulation, remodeling can also occur in the limbic system which, after prolonged use, tends to associate any sense of pleasure to tramadol use. After downregulation and remodeling have occurred, the normal levels of dopamine present in the brain will be unable to stimulate these pleasure centers as was the case during tramadol use. Dopamine can even become so downregulated that someone will have a reduced ability to experience any pleasure at all without using tramadol, and this is the cause of anhedonia during withdrawal. This process is capable of reversing itself, but again, this is a slow process and will take time. 27, 28, 29
The intensity of tramadol withdrawal, while on average less intense than withdrawal from other opioids, shows some variability between individuals. While the factors that contribute the most are directly related to tramadol use habits, other factors that can play a role include genetics, age, and underlying health issues. Depending on these factors, both the intensity and the duration of tramadol withdrawal can be affected. While some people may recover quite quickly and fully, others may experience persistent symptoms that may last for years in some cases.
Some of the factors that can greatly contribute to the intensity and the duration of tramadol withdrawal symptoms include:
The largest contributors to the intensity and duration of the symptoms of tramadol withdrawal are related to someone specific tramadol use habits. The more tramadol someone uses, the more downregulation occurs in the brain. The more downregulation occurs, the worse the symptoms will be when someone stops using tramadol. After downregulation begins a further process of neurological remodeling can occur. The longer someone uses tramadol, the more complete this process of downregulation becomes, therefore the longer symptoms will persist after someone stops using tramadol.
Different from most other opioids, tramadol exhibits some significant metabolic differences between people. This has to do with liver function in general, which can be affected by age or disease, and specific genetics, which can alter the way certain metabolic enzymes are expressed in the liver. As far as general liver function is concerned, tramadol is often metabolized slower by the elderly or people who have impaired liver function. This can result in a slower onset of tramadol withdrawal symptoms and subsequently a longer withdrawal period. That also means, however, that the symptoms of withdrawal will likely not be as severe. Someone’s genetic background can have a significant impact on the speed of tramadol metabolism. Specifically, people who have mutations to CYP 2D6 liver enzymes will metabolize tramadol much slower than the general population. This can also lead to a longer, although typically less intense withdrawal period. 30, 31, 32, 33
The existence of co-occurring mental health disorders can contribute to both the intensity and the duration of tramadol withdrawal symptoms, although this contribution is very indirect. Since depression and anxiety are such common symptoms of tramadol withdrawal, if someone were to have a pre-existing mental health condition involving one of these symptoms, they may experience heightened versions during withdrawal. Finally, these psychological symptoms may linger for longer if someone had an issue with depression or anxiety before tramadol use.
Breaking free from tramadol addiction can be a difficult process, and help is often required to make this a reality. Thankfully, there are a variety of treatment options available to help reduce the risks and discomfort as well as improve someone’s chances of long-term recovery. There has also been substantial research in recent years towards developing new and more effective treatments for opioid withdrawal due to the opioid crisis in America and other western countries. Some of the most effective treatment options come in the form of a combined medication-therapeutic approach and offer better long-term outcomes than either approach individually.
The FDA has recently approved the first non-opioid medication for the treatment of opioid withdrawal in the form of lofexidine (Lucemyra). This medication is intended to treat most, if not all, symptoms of opioid withdrawal at once. Aside from this medication, there are many other options that can effectively treat one or more symptoms of tramadol withdrawal as they arise.
Some of the medication classes that are most commonly used to treat tramadol withdrawal symptoms include:
These are just some of the broad categories of medications used, and some categories contain many individual medications. Everyone responds to medications a little differently, so finding the right one may take some time. Having trained medical professionals at a tramadol detox center to advise, monitor, and adjust medications as needed can shorten the time until the most effective medication can be found.
Aside from medications that can reduce the discomfort, risks, and potential dangers of withdrawal, therapies have been found very effective at treating the psychological symptoms of tramadol as well. Therapeutic practices and techniques can help someone deal with the stresses of withdrawal and help them develop new habits for a new life after tramadol addiction.
Some of the therapies most commonly used in the treatment of tramadol withdrawal symptoms include:
Similar to medications, different people will respond to different therapeutic techniques uniquely. Also, depending on any past trauma or unresolved issues they may be dealing with, certain approaches may be more effective than others. Again, having the trained clinicians and psychologists at a tramadol detox center can be a massive aid to recovery. The guidance, support, and care provided can be extremely beneficial to someone’s chances of long-term recovery.
Tramadol addiction can be extremely destructive to someone’s life, but recovery is possible. The behaviors, habits, and patterns of thinking that have led someone into addiction do not have to continue. Help is often required to make the necessary changes that can let someone live a life free of tramadol or other drug use. That help is available and all it takes to obtain it is the courage to ask for help, and the willingness to receive that help. Addiction doesn’t have to be a lifelong struggle; recovery is possible and it can start today.
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