Methadone Withdrawals

Opioid use disorder (OUD) is a chronic, relapsing condition, often associated with legal, interpersonal, and employment problems. Opioids can lead to physical dependence. Over time, more of the drug is needed for the same effect. This is called drug tolerance. In the absence of opioids, a distinct group of symptoms will emerge. The principal site in the brain that triggers the onset of opioid withdrawal syndrome is the locus coeruleus (LC) at the base of the brain. Neurons within the LC are noradrenergic (NAergic) and have an increased number of opioid receptors. The locus coeruleus region is the main source of NAergic innervation of the limbic system and cerebral and cerebellar cortices. The LC plays a central role in opioid dependence and withdrawal and its activity is regulated by opioids. Research has shown that gray matter and nucleus raphe magnus are involved in the presentation of opioid withdrawal syndrome. There are three types of opioid receptors; mu (μ), delta (𝛿), and kappa (𝜅), each composed of G proteins. Binding to these receptors reduces adenylyl-cyclase production as indicated by a drop in cyclic adenosine monophosphate levels (cAMP). A reduction in the availability of opioids results in the opposite scenario.

Opioid withdrawal occurs when a patient who is dependent on opioids suddenly reduces or stops taking opioids as evident by an overshoot in the amount of cAMP produced in the LC. This can also be caused when a patient has an opioid in his/her system and is given an opioid partial agonist like buprenorphine or antagonists like naloxone or naltrexone. Methadone is a synthetic opioid agonist that eliminates withdrawal symptoms and relieves drug cravings by acting on the mu (μ) opioid receptors of the LC—the same receptors that other opioids such as heroin, morphine, and opioid pain medications bind. This results in a downregulation of the amount of cAMP produced. The pharmacokinetics of methadone varies greatly from person to person; so, after the administration of the same dose, considerably different concentrations are obtained in different subjects, and the pharmacological effect may be too small in some patients, too strong and prolonged in others. Methadone can be detected in the blood 15-45 minutes after oral administration, with peak plasma concentration at ~ 3 hours. Plasma concentrations of methadone decrease in a biexponential manner, with a mean value of around 22 hours (range 5-130 hours) for elimination half-life. Methadone is mostly metabolized in the liver; the main step consists in the N-demethylation by CYP3A4 to EDDP (2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine), an inactive metabolite. It is ultimately eliminated from the body via renal and fecal excretion. The activity of CYP3A4 varies considerably among individuals, and such variability is responsible for the large differences in methadone bioavailability. CYP2D6 and probably CYP1A2 are also involved in methadone metabolism. During maintenance treatment with methadone, treatment with other drugs may be necessary due to the frequent comorbidity of drug addicts: psychotropic drugs, antibiotics, anticonvulsants, and antiretroviral drugs, which can cause pharmacokinetic interactions. Antiretrovirals are CYP3A4 inducers in the liver thereby reducing the levels of methadone. In turn, this causes cravings and withdrawal symptoms as evidenced by an increase in cAMP in the LC. Buprenorphine (found together with Naloxone in Suboxone) is also metabolized by CYP3A4, and may undergo the same interactions as methadone. Therefore, methadone maintenance treatment (MMT) is not a “one glove fits all” solution and requires medical expertise to reach the optimal dose that prevents opioid cravings and withdrawal while at the same time, monitoring for excessive sedation.

• Chills
• Fever
• Anxiety
• Muscle aches and pains
• Nausea
• Vomiting
• Sweating
• Rapid heartbeat
• Stomach cramps
• Irritability
• Paranoia
• Diarrhea
• Cravings
• Insomnia
• Hallucinations
• Depression

How long it takes to become physically dependent on opioids varies with each person. When the person stops taking a supply of opioids, withdrawal symptoms emerge. The duration of opioid withdrawal can be loosely divided into both physical & psychological symptoms. The former typically subside by 10 days and the latter can continue for weeks following the last opioid dose.

Withdrawal Timeline:

• Early withdrawal period: 6 – 30 hours after last opioid use
  • Muscular aches and pains, rhinorrhea (runny nose), insomnia, yawning, anxiety, sweating, fever, and elevated blood pressure. 
    
    
• Late withdrawal period: 72 hours – 7 days after last opioid use
  • Diarrhea, nausea, vomiting, cravings for the opioids, stomach cramps, and depressed mood
    
    
• Post-Acute Withdrawal Symptoms (PAWS) – 7 days+
  • Some people may experience symptoms longer than 7 days, these include persistent depression, anxiety, and opioid cravings.

Detoxification from methadone maintenance treatment (MMT) program is a highly personal decision made by the patient with the assistance of the physician.  In general, the dose of methadone should not be reduced by more than 10% per week.  However, if the patient is switching to Suboxone, then the rate of detoxification of methadone can be increased, as Suboxone is added concurrently in microdosing doses, usually over a 7-10 day span.

Medications demonstrated to be effective for OUD & opioid withdrawal are methadone (a full opioid agonist), buprenorphine (a partial agonist), and naltrexone (an opioid antagonist). More recently, slow-release oral morphine (SROM/Kadian) have also been used with success.  Methadone and buprenorphine act by suppressing opioid withdrawal symptoms and attenuating the effects of other opioids. Oral methadone has the strongest evidence for effectiveness. Longer duration of treatment allows restoration of social connections and is associated with better outcomes. During the withdrawal phase, Clonidine can be used to reduce sympathetic overdrive of certain brain chemicals that cause the following in withdrawal: sweats, hot flashes, watery eyes and restlessness.  Clonidine may also help with reducing anxiety and reducing the duration of opioid detoxification process.sweating, hot flashes, watery eyes, and restlessness. Non-steroidal anti-inflammatory drugs (NSAIDs) like Ibuprofen, Naproxen….etc, can be used to reduce the pain associated with opioid withdrawal.

Relapse is prevented by attending a recognized addiction out-patient clinic like Road to Recovery (RTR) Health Clinics on a regular basis (admin@roadtorecovery.clinic).  Counseling and support services arranged through the clinic will only further increase your chance of long-term success in the program.