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Methadone Withdrawal Timeline

Medically Reviewed By: Benjamin Caleb Williams RN, BA, CEN

Written By: Phillippe Greenough

Article Updated: 01/24/2021

Number of References: 19 Sources

Methadone withdrawal, while not as intense as withdrawal from other opioids, is still unpleasant and is much longer-lasting. The timeline for methadone withdrawal can last for several weeks in some cases and includes symptoms such as deep depression, diarrhea, deep aches, anxiety, and insomnia. In this article we will look into the specific symptoms, the methadone withdrawal timeline, and the particular effects of methadone withdrawal in both the brain and body.

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Methadone Withdrawal Symptoms

Withdrawal from methadone is similar to withdrawal from other opioid drugs in terms of the specific symptoms, although there are differences in the timeline and the intensity of these symptoms that make methadone withdrawal a distinct syndrome. The extremely long half-life of methadone causes the withdrawal symptoms to appear much later after ceasing use when compared to other opioids. Additionally, the withdrawal symptoms will persist for much longer than they would from any other opioid. Due to some functional differences in the way methadone works, there is also a huge variation in withdrawal duration and intensity between different people.

Methadone withdrawal can be divided into two distinct phases; acute and post-acute. Acute methadone withdrawal is the phase immediately after someone stops using the drug, while post-acute is several months after the acute phase. These two phases, while distinct, may share symptoms, but the acute phase is by far the most intense and is characterized by primarily physical symptoms. The post-acute phase exhibits strictly psychological symptoms and is very long-lasting, typically lasting many months.

The acute phase is characterized by sometimes severe physical symptoms and gradually intensifying psychological symptoms. Due to methadone’s extremely long half-life, it may take between two and three days after someone stops using methadone for these symptoms to begin appearing. These symptoms may begin quite mild but will escalate over the first week or two and the physical symptoms typically reach their peak around the middle or end of the second week. There is great variability in the duration of this phase between people, but the average duration is between two and three weeks.

Week 1

Due to methadone’s very long half-life, withdrawal symptoms will only begin between 24 to 36 hours after the last time someone used the drug. The first symptoms are usually increasing anxiety or panic and sweating. The next symptoms may be light shakes and a combined feeling of hot and cold, usually described as someone’s skin feeling cold while their insides are very hot. Someone may then begin to experience muscle and joint aches and sweating will continue to increase along with a constantly runny nose which is very watery. The second day after withdrawal symptoms have appeared will exhibit frequent diarrhea, stomach cramps, and insomnia later that night. Restlessness will become more pronounced and heart rate and blood pressure may begin to increase around this time. These symptoms will slowly amplify over the course of the first week.

Some symptoms of methadone withdrawal that may be expected during the first week could include:

  • Increasing Anxiety
  • Deep Depression
  • Mood Swings
  • Diaphoresis (constant sweating)
  • Rhinorrhea (extremely runny nose)
  • Shakes and Tremors
  • Pain in the Muscles, Joints, or Bones
  • Nausea, Stomach Cramps, and Diarrhea
  • Chills and Hot Flashes
  • Severe Insomnia
  • Intense Cravings for Methadone
  • Lack of Appetite
  • Repeated Yawning
  • Extreme Restlessness and Irritability
  • Fatigue and Lethargy
  • Tachycardia (fast heart rate)
  • Hypertension (high blood pressure)

Week 2

The second week will be extremely uncomfortable and marks the peak intensity of symptoms. While they may still be escalating at the beginning of week two, they may reach their maximum in the middle or end of the week. While anxiety will have been high and constant, depression and wild mood swings may begin to appear around the beginning of week two. The prolonged lack of sleep and food combined with frequent diarrhea will worsen the subjective experience of the entire ordeal. Also, even though someone is extremely restless, they will have absolutely no energy or motivation to do anything other than lay in bed. These physical symptoms will increase through part of the second week, and once reaching their peak should begin to resolve slowly. The first to disappear is usually muscle aches and diarrhea, followed by a slow resolution of the rest of the symptoms.

Some of the symptoms of methadone withdrawal that can persist into the second week may include:

  • Increasing Anxiety
  • Deep Depression
  • Mood Swings
  • Diaphoresis (constant sweating)
  • Rhinorrhea (extremely runny nose)
  • Mild Tremors
  • Strong Cravings for Methadone
  • Aches in the Muscles, Joints, or Bones
  • Diarrhea
  • Chills and Hot Flashes
  • Insomnia
  • Reduced Appetite
  • Repeated Yawning
  • Restlessness and Irritability
  • Fatigue and Lethargy
  • Tachycardia (fast heart rate)
  • Hypertension (high blood pressure)

Weeks 3 & 4

While the physical symptoms may have begun to decrease, the psychological symptoms are often still present and usually quite intense. Insomnia will most likely be present as will constant yawning, but most of the remaining physical symptoms may be much reduced. Stomach issues may still persist in a mild form by this time. Anxiety and depression are usually still present and mood swings can begin mild but may escalate over the course of the third week. The fourth week is marked by an almost total resolution of the physical symptoms. Yawning and insomnia may be present but are much less intense than they were in the weeks prior. The main challenges are going to be psychological during this time. Anxiety may have increased during the third week and is still very much present; it may manifest as generalized anxiety as well as social anxiety. The mood swings may have reduced or fully resolved by this time, however, depression and cravings are usually still severe at this point. This time is crucial to enter or continue treatment, as many methadone relapses occur shortly after the physical symptoms have resolved. The psychological symptoms may be helped through medications and therapy, but it will usually take several months before they resolve naturally. They will reduce over the next few months, but this is a slow and oftentimes uncomfortable process.

  • Increasing Anxiety
  • Deep Depression
  • Mood Swings
  • Diarrhea
  • Minor Chills and Hot Flashes
  • Mild Insomnia
  • Reduced Appetite
  • Repeated Yawning
  • Irritability
  • Minor Fatigue
  • Cravings for Methadone

Post-Acute Withdrawal

The post-acute phase, while much less intense, is extremely long-lived. The physical symptoms may be gone for the most part, but there will still be psychological symptoms lingering for months. These will decrease with time, but the duration and their persistence can be infuriating and very demoralizing.

Some of the most frequently reported symptoms of post-acute methadone withdrawal include:

  • Severe Anxiety
  • Deep Depression (with or without suicidal thoughts)
  • Insomnia
  • Profound Lack of Energy and Motivation
  • Dramatic Mood Swings
  • Cravings for Methadone

While these symptoms will resolve over time, it can take many months to notice relief. It is highly recommended to seek psychiatric support and counseling during the post-acute phase. If left untreated, these symptoms can easily drive someone to seek relief in methadone use, starting the whole cycle over again.

What Factors Influence the Intensity of Methadone Withdrawal?

There are several factors which can affect the intensity and the duration of methadone withdrawal. Some of these are decided at conception or birth, while others are voluntary behaviors. Some people may experience fairly mild symptoms of methadone withdrawal which resolve quickly, while other people will suffer from severe symptoms that persist for long periods.

Some factors which can greatly affect the intensity and duration of methadone withdrawal include:

  • Genetics
  • Body Mass Index
  • The amount of methadone someone used
  • The length of time that someone used methadone
  • Co-occurring mental health issues

Genetics is an involuntary factor that probably plays an indirect role regarding the intensity and duration of methadone withdrawal. Aside from the genetic predisposition to addiction, methadone metabolism is strongly influenced by genetic factors. This is evidenced by the extreme variability of methadone’s half-life of between 5 to 130 hours. Additionally, since methadone is highly fat-soluble, someone’s genetic inclination to store fat may affect the intensity and duration of withdrawal as well. Methadone withdrawal will not begin in earnest until levels of the drug have dropped below a certain point for long enough for their brain to begin to heal the disruptions it produced. Due to this, a person’s metabolism and body fat percentage can have a great impact on this timeline.

The largest voluntary factor that contributes to methadone withdrawal is certainly someone’s methadone using habits. This includes the amounts someone used as well as the length of time that someone used methadone, although these may affect different aspects of withdrawal. The amounts someone used has a direct impact on the degree of downregulation the brain will perform. This then leads to more intense withdrawal symptoms, and the more downregulation that occurs, the greater the discomfort when methadone is finally removed. The length of time that someone used methadone may affect the intensity, but it absolutely affects the duration of withdrawal. The longer methadone is used, the more complete the downregulation process becomes, and subsequently the more neurological remodeling occurs. Remodeling is the process of the brain making structural changes to better operate in an opioid-downregulated environment. The longer someone uses methadone, the more remodeling occurs, and subsequently, the longer they will experience withdrawal symptoms.

Co-occurring mental health issues also contribute, but in a very indirect way. Similar to a genetic predisposition for addiction, mental health issues such as depression may encourage methadone use as it may give someone a temporary respite from their symptoms. This can accelerate someones using habits and push them further into methadone addiction in a shorter time than someone who suffered no such mental illness. The relationship is very tangential, but there is certainly an influence present.

More About Methadone Addiction

To get a better understanding of methadone withdrawal, it will be helpful to know more details about exactly how methadone works. Methadone is a fully synthetic opioid painkiller that exerts its effects through strong stimulation of the μ (Mu), κ (Kappa), and δ (Delta) opioid receptors, which is common among opioids. Methadone differs from other opioids in that it also acts as an inhibitor of certain glutamate receptors as well as acting as a reuptake inhibitor for serotonin and norepinephrine. This could contribute to the painkilling, euphoric, and depressant effects of methadone use.

The largest contributor to methadone withdrawal is the effect it produces on the opioid system in the brain. The opioid system plays an important role in a variety of neurological and physical functions such as emotional regulation, perception of pain, as well as heart and digestive function. When someone uses methadone, the drug will stimulate this system much more intensely than the body’s own opioids (known as endogenous opioids) are capable of. Through chronic use, the body and brain will make changes to the opioid system in an effort to protect them from cell damage or cell death. This is known as downregulation and is essentially the brain turning down the sensitivity of these opioid receptors to protect them from overstimulation, or “neurotoxic” brain damage.

Downregulation is one part, but the effects methadone has on the glutamate system is a somewhat opposite effect. Glutamate is an excitatory neurotransmitter, and methadone reduces the effect of glutamate by it’s “antagonist” activity at the NMDA glutamate receptors. This means that methadone use directly reduces the stimulation that glutamate produces when it binds to receptors. After chronic under stimulation of glutamate receptors, the brain will undertake “upregulation” at glutamate receptors to restore balance. This is the act of increasing the sensitivity of these receptors since there are chronically low levels of glutamate stimulation.

These effects of selective up- and downregulation can conspire to produce an intense and extended methadone withdrawal experience. Once these regulation processes have been performed and then methadone use ceases, the body and brain will be out of balance. The opioid system will be severely understimulated, while parts of the glutamate system will be overstimulated. These effects can compound themselves since the opioid system helps dampen and moderate nerve signals, while the glutamate system helps to amplify and increase nerve signals. This is a synergy of negative effects that can produce a variety of unpleasant symptoms.

The Importance Of Methadone Detox

The effects of methadone withdrawal are extremely unpleasant, and it often requires help to make it through this sometimes painful process. The help provided by methadone detox centers can be invaluable to someone’s journey of recovery. Having trained medical professionals for medical supervision, medication management, and therapy during methadone withdrawal and detox can make all the difference in the world.

Methadone Detox Centers

Article References (In Addition to 5 in-article references)

  1. 1 Drug and Alcohol Dependence: Ethnic and Genetic Factors in Methadone Pharmacokinetics - A Population Pharmacokinetic Study
  2. 2 American Society of Addiction Medicine: National Practice Guideline for the Use of Medications in the Treatment of Addiction Involving Opioid Use
  3. 3 Clinical Infectious Diseases: Absence of Opioid Withdrawal Symptoms in Patients Receiving Methadone and the Protease Inhibitor Lopinavir-Ritonavir
  4. 4 Australian Government Department of Health: The Principles of Methadone Maintenance Therapy
  5. 5 The BMJ: Methadone - Applied Pharmacology and Use as Adjunctive Treatment in Chronic Pain
  6. 6 Frontiers in Pharmacology: Gender Differences in Pharmacokinetics and Pharmacodynamics of Methadone Substitution Therapy
  7. 7 Cellular and Molecular Life Sciences: Presynaptic NMDA Receptors Control Nociceptive Transmission at the Spinal Cord Level in Neuropathic Pain
  8. 8 Clinical Pharmacokinetics: Interindividual Variability of the Clinical Pharmacokinetics of Methadone
  9. 9 Anesthesiology: Methadone Pharmacokinetics are Independent of Cytochrome P4503A (CYP3A) Activity and Gastrointestinal Drug Transport - Insights from Methadone Interactions with Ritonavir/Indinavir
  10. 10 Clinical Pharmacology in Drug Development: Current Concepts in Methadone Metabolism and Transport
  11. 11 Scientific Reports: Methadone Induced Damage to White Matter Integrity in Methadone Maintenance Patients - A Longitudinal Self-control DTI Study
  12. 12 Journal of Pain and Symptoms Management: Pain Responses in Methadone-Maintained Opioid Abusers
  13. 13 Neuropsychopharmacology: High-Dose Methadone Maintenance in Rats - Effects on Cocaine Self-Administration and Behavioral Side Effects
  14. 14 Pharmacological Reports: Effects of Morphine and Methadone Treatments on Glutamatergic Transmission in Rat Frontal Cortex

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