“Men succeed when they realize that their failures are the preparation for their victories.”
– Ralph Waldo Emerson



It is recommended to first read the following sections to become familiarized with some of the terms and concepts related here:


Neurobiology of Pain

Neuropathic Pain


Neurobiology of Opioids

Opioid Tolerance

Opioid Induced Hyperalgesia


Also see:



Oxymorphone (Opana)




Definitions and Terms Related to Pain


Key to Links:

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Red text – another page on this website

Blue text – Journal publication



Opioids – Methadone

Methadone, a synthetic opioid best known for treatment of opioid addiction, is also very effective for chronic pain. Patients experiencing inadequate pain relief or side effects while on other opioids may benefit from a transition to methadone.  Additionally, unique pharmacological properties make methadone a useful option for some people with chronic pain.


When should methadone be used for pain instead of other opioids?

Because methadone is one of the most potent opioid pain medicines available, it is generally reserved for those chronic pain patients who have developed a high tolerance to opioids based on years of use. As a result of this tolerance, many of the more commonly available opioids such as hydrocodone or oxycodone are no longer effective or extremely high doses are required to achieve pain relief. The advantages of methadone are numerous. It is affordable, even for those without insurance. It’s pain relieving benefits are rapid in onset and are longer lasting than most other opioids, lasting up to 12 hours without the need for a time-release formulation.


Methadone appears to be one of the most effective opioids in managing neuropathic pain, the sharp, burning or stabbing pain thought to be related to irritated or dysfunctional nerves. There is evidence that the build up of tolerance with methadone is one of the slowest of all opioids. These benefits associated with methadone are thought to be related to methadone’s ability to block the NMDA receptor – a mechanism similarly reported with levorphanol. The extent to which methadone blocks NMDA has recently been called to question, suggesting other possible mechanisms are at hand for these benefits. For more information, see below: “Neurobiology of Methadone Analgesia.”


What are the disadvantages of methadone as a pain reliever?

Methadone has a social stigma attached to it because of it’s history of being used to treat opioid addiction, especially heroin, which makes some people uncomfortable associating themselves with it. Apart from education, there is little way around this except perhaps using the original brand name for methadone: “Dolobid.”


The main pharmacologic advantage AND disadvantage of methadone lies in its potency. While It offers the same risks and side effects common to all opioids, because it is strong, one must be careful to follow the physician’s dosing instructions carefully. There are, however, some special precautions advised for those taking methadone.


What are the special precautions advised when taking methadone?

Methadone has certain characteristics that require added caution for it’s safe use. The metabolism of methadone is complex which makes it potentially susceptible to drug interactions with other prescription medications, herbal and nutritional supplements or even grapefruit juice, which can lead to higher methadone blood levels than otherwise expected and result in accidental overdose. People are very susceptible to the effects of genetic variants that superimpose on the potential drug interactions with other medicines. The genetic variants, when identified, can provide significant safety advantages when prescribing methadone by allowing for better prediction of risk for drug or food interactions.  For this reason, Dr. Ehlenberger strongly recommends genetic testing accompany prescribing methadone.


Also, when a dose increase of methadone is initiated it may take up to a full week before the rising blood level equilibrates, so that any increase in dosing of methadone should be done slowly and under a physician’s direction. For additional information about dosing precautions, See below: “Pharmacologic Properties.”


Another characteristic of methadone is that it may disrupt the conduction of electrical impulses in the heart, which allow the heart to beat rhythmically (measured by the QTc interval on an EKG). This disruption can lead to palpitations or blackout spells, even sudden death. However, while such disruptions are thought to be rare, the risk for this complication appears to be highest in the elderly, those with heart disease,those on high doses of methadone, those with electrolyte abnormalities and those taking other medications that also prolong the QTc interval. For this reason, your physician will want to monitor your EKGs for evidence of this effect while taking methadone. Due to genetic variants, some people may be at greater risk for this complication of QTc prolongation. For this reason also, Dr. Ehlenberger strongly recommends genetic testing accompany prescribing methadone.


For those patients with sleep apnea, especially untreated sleep apnea, or those at risk for sleep apnea, the use of methadone or any potent opioid poses a potential risk. Sleep apnea, whether obstructive sleep apnea as usually manifest as loud snoring, or central sleep apnea as related to stroke, central nervous system disease or use of sedatives is characterized by episodes of pausing in breathing while asleep. These episodes are associated with a drop in blood oxygen and can lead to heart attacks, strokes or respiratory arrest while asleep.


All opioids and sedatives have the potential to suppress breathing causing additional compromise to oxygen levels while asleep and this potential is both dose related and related to the potency of the opioid. Due to methadone’s potency it can be a dangerous contributor to complicating sleep apnea. Therefore, if one is at risk for sleep apnea as manifest by loud snoring, excessive daytime sleepiness, observed episodes of respiratory pauses while asleep, it is important to notify your physician who may wish to have a sleep study (polysomnogram, PSG) performed to establish safety of prescribing opioids and/or other sedatives.


For the reasons above, it is important that any physician prescribing medications to someone taking methadone be aware of these possible drug interactions and concerns. Since not all physicians are experienced with managing patients taking methadone, we strongly advise patients taking methadone to always call our clinic to notify us if any new medications are added to your regimen so that we can advise you of any special precautions that should be taken to avoid dangerous drug interactions.


How should this medicine be taken?

Methadone may be taken every 8-12 hours, or more frequently, depending on how your doctor advises. All the usual precautions associated with taking opioids apply to methadone: there is potential toxicity when taking other sedative drugs especially the benzodiazepines such as Xanax, Klonopin and Valium, antidepressants and alcohol.


When your doctor changes your dose of methadone, please follow his instructions carefully as the dosing of methadone has many variables that can affect safety. Ask your doctor if you have any questions about how much methadone you should take or how often you should take it.


Do not stop taking methadone without talking to your doctor. Your doctor will probably want to decrease your dose gradually. If you suddenly stop taking methadone, you may experience withdrawal symptoms such as restlessness, teary eyes, runny nose, yawning, sweating, chills, muscle pain, nausea, diarrhea and widened pupils.


Methadone Transition

When converting from another opioid to methadone, the process should be done slowly and tremendous care taken when determining equivalent dosages. Please discuss this process with your physician.


General Precautions

The risk that you will experience serious or life-threatening side effects of methadone is unlikely but greatest when you first start taking methadone, when you switch from another narcotic medication to methadone and when your doctor increases your dose of methadone. Your doctor will likely start you on a low dose of methadone and gradually increase your dose. Communicate closely with your doctor during this time.


Follow the directions on your prescription label carefully and ask your doctor or pharmacist to explain any part you do not understand. Take methadone exactly as directed. Do not take more methadone or take methadone more often than prescribed by your doctor. As you take methadone to control pain, your pain may return before it is time for your next dose of methadone. If this happens, do not take an extra dose of methadone. You will still have methadone in your system even after the pain relieving effect of the medication wears off, so If you take extra doses, you may accumulate too much methadone in your system and you may experience life-threatening side effects. Be aware that the pain relieving effects of methadone will last longer as your treatment continues for a longer time. Talk to your doctor if your pain is not controlled during your treatment with methadone or if you have questions about the risks of taking methadone.


What special dietary instructions should I follow?

Talk to your doctor about eating grapefruit or drinking grapefruit juice while taking this methadone as this may sometimes cause a rise in your methadone blood level and result in dangerous side effects. Star fruit may also have a similar effect.


What should I do if I forget a dose?

If your doctor has told you to take methadone regularly, take the missed dose as soon as you remember it. However, if it is almost time for the next dose, skip the missed dose and continue your regular dosing schedule. Do not take a double dose to make up for a missed one.


What storage conditions are needed for methadone?

Keep this medication in the container it came in, tightly closed, and in a safe, locked location out of reach of children and inaccessible to anyone but those managing your medications with you. Store methadone at room temperature and away from excess heat and moisture (not in the bathroom). Keep track of how many tablets you have left so you will know if any go missing. To dispose of any medication that is outdated or no longer needed, grind it into powder, mix it with kitty litter or coffee grounds and place it in a closed container in the trash or flush it down the toilet (see Safe Disposal of Medicines).


Methadone may cause side effects:

Like all opioids, methadone may cause side effects. These side effects are likely to be mild and generally avoided when methadone is started at a very low dose and slowly increased under your physician’s guidance. Constipation, a common side effect with opioids, appears to be less of a problem with methadone (like fentanyl) compared with morphine and oxycodone. However, tell your doctor if any of these symptoms are severe or do not go away:






   loss of appetite

   weight gain

   stomach pain

   dry mouth



   difficulty urinating

   swelling of the hands, arms, feet, and legs

   mood changes</p >

   vision problems

   difficulty falling asleep or staying asleep

   decreased sexual desire or ability

   missed menstrual periods


Some side effects can be serious. If you experience any of the following symptoms, call your doctor immediately:






Methadone may cause other side effects. Call your doctor if you have any unusual problems while you are taking this methadone.


Opioid Induced Hyperalgesia (OIH) and Methadone

Research indicates that short term and long term use of opioids, including methadone, can lead to increased sensitivity to painful stimuli (hyperalgesia). Almost all of the studies exploring this with methadone have evaluated patients on methadone for addiction, not pain, and the dosages therefore may have tended to be higher than doses used commonly in pain management.


One 2008 study compared OIH in methadone and morphine pain patients. In this study, patients treatment with either methadone or morphine showed lower threshold and decreased tolerance to cold pain. There was no hyperalgesia to mechanical or electrical pain nor was there increased allodynia. It should be noted that this study evaluated cold pain through use of a cold-pressor test in which subjects tested were evaluated by placing a blood pressure cuff on their arms, pumping the cuff high enough to compromise arterial flow to the arm, then immersing the arm in freezing cold water and assessing pain response. While this procedure may suggest increased sensitivity to cold-induced pain, it represents a far stretch towards defining this as clinically relevant to patients taking opioids for chronic pain.


Furthermore, while some studies have identified methadone treatment as contributing to the development of hyperalgesia, other studies have identified methadone as an opioid of choice when confronting the problem of OIH because of methadone’s NMDA antagonist properties which have been shown to reduce or reverse the OIH that has developed with use of other opioids. What is certain at this point is time is that the question of clinical relevance of OIH with the use of methadone in either pain or addiction remains unanswered.

See: Opioid Induced Hyperalgesia (OIH).


Pharmacologic Properties

Methadone is rapidly absorbed after swallowing. Time to peak blood concentration, however, varies from one to five hours. Methadone induced slowing of stomach emptying may account for longer time to peak concentration in chronic users. Oral bioavailability of tablets is approximately 60%–70%, but wide variation among patients exists. The analgesic (pain) benefit of a dose begins within 30 to 60 minutes after swallowing and generally lasts for four to eight hours. While the pain benefits may last only up to 6-8 hours, methadone stays in the blood for many hours, sometime days before it is metabolized by the liver and eliminated. How long it stays in the blood varies considerably from individual to individual based on genetic and other factors. It is for this reason that caution is necessary when taking methadone, especially when first starting it, as it is not always possible to predict an individual’s response to methadone. Due to these individual variations with methadone, the FDA recommends the dosing interval for pain be every 8-12 hours.


Once absorbed into the blood, most methadone binds to proteins in the blood and a balance is established between the protein-bound methadone and the unbound, free methadone in the blood. This is important because it is the free methadone that provides the therapeutic benefits and various circumstances can alter this protein-bound and free methadone balance. Some disease states like cancer can increase the amount of protein bound methadone causing a reduced amount of free methadone. Some medications can displace the protein binding causing the free levels to go up, including propranol, erythromycin, clarithromycin, Vitamin E and many of the NSAIDS (Ibuprofen and Ketoprofen) and certain antidepressants.


Variable Potency Based on Dose

Methadone exhibits a unique property that requires heightened caution when prescribed. While other opioids maintain the same potency, mg for mg, regardless of dosing, methadone exhibits higher potency/mg when it is taken at higher doses:


Morphine Equivalency for Methadone:

1-20 mg/day   – 4.0

21-40 mg/day   – 8.0

41-60 mg/day   – 10.0

61+ mg/day   – 12.0


For example, when taking up to 20mg of methadone/day,  each mg of methadone is equivalent to taking 4 mg of morphine. But at the higher dose of taking 30mg of methadone/day, each mg of methadone is equivalent to taking 8 mg of morphine and if you are taking more than 60mg of methadone/day, each mg of methadone is equivalent to taking 12 mg of morphine.


This means that when you increase your daily dose of methadone, you must proceed slowly or there is a significant risk of accidentally overdosing. Also remember, it takes up to 4 days for an increased dose to stabilize blood levels so one should not increase methadone dosing faster than every 4 days until the full effect of the increase can be experienced.</p >


As noted above, methadone’s potency is enhanced at higher doses, one of the contributing factors to the complexity of prescribing methadone. Follow your physician’s recommended dosing instructions carefully.


Genetic Testing

At Accurate Clinic we highly recommend genetic testing for our methadone patients. Through testing our patient’s DNA with a simple oral swab of saliva from the cheek, an individual’s ability to metabolize methadone and other medications by the liver can be evaluated. This information provides important insights as to how a patient may respond to methadone and where side effects or drug interactions may be predicted, allowing for substantial safety benefits in prescribing.


Neurobiology of Methadone Analgesia

Analgesia via Mu-Opioid Agonism

Methadone is complex but actually very interesting in how it benefits treating pain. Methadone as a molecule exists in two forms, each a mirror image of the other, D-methadone and L-methadone. A prescription tablet of methadone contains 50% of each form. The L-methadone form relieves pain by interacting with the mu-opioid receptor but the D-methadone has little to no activity for the mu-opioid receptor and is not thought to contribute to analgesia, at least through the mu-opioid receptor.


Analgesia via NMDA Antagonism

However, both D- and L- forms have equal activity as inhibitors of NMDA receptors and this activity is thought to improve analgesia by reducing hyperalgesia, allodynia and central sensitization. Inhibition of NMDA is also believed to reduce opioid tolerance, thereby contributing indirectly to improved pain control.


Studies of the evolution of tolerance to long term (>20 years) methadone treatment in methadone maintenance programs showed a 1.5 fold increase dose needed to maintain the beneficial effects of treatment over 20 years. This 1.5 fold increase is significantly less than commonly seen with other opioids uesed in pain management, especially oxycodone, where increases in tolerance result in 5 fold or greater increased doses. While the “beneficial” effects were not specifically defined, the implication was referencing control of cravings which may differ from tolerance to analgesia. “Higher” doses of methadone were sometimes required, exceeding 200mg/day or even higher.


Analgesia via Serotonin and Norepinephrine Reuptake Inhibition (SNRI)

A lesser understood activity of methadone includes it’s ability to inhibit the reuptake of serotonin and norepinephrine in the nerve synapses, the same mechanism by which the antidepressants Cymbalta (duloxetine), Savella (milnaciprin) and Effexor (venlafaxine ) work. This action (on the descending pathways that inhibit pain perception – see Neurobiology of Pain) is believed to be how these antidepressants also reduce neuropathic pain in addition to their anti-anxiety and antidepressant effects. It is also believed that in addition to the NMDA antagonism, this SNRI activity is responsible for the usefulness of methadone in managing neuropathic pain.


Of note, levorphanol is another opioid that shares these same three analgesic benefits with even greater NMDA antagonism benefit, making it another option to methadone. Although levorphanol has been in use for many years, it has recently been re-introduced after a gap in manufacturing and is now again available. Because levorphanol offers the same benefits as methadone with fewer safety concerns, for many people levorphanol would be the favored option.

See: Levorphanol



Methadone – Patient Information

  1. Methadone – MedlinePlus Drug Information
  2. Methadone Product Information
  3. Methadone – Drug Information
  4. Methadone – Drug Interactions


Methadone – Overviews

  1. Methadone- applied pharmacology
  2. Methadone- does stigma play a role as a barrier to treatment of chronic pain
  3. Is Levorphanol a Better Option than Methadone – 2015
  4. Trends in Methadone Distribution for Pain Treatment, Methadone Diversion, and Overdose Deaths — United States, 2002–2014</a ></l i>


MethadoneDrug Interactions

  1. Methadone – Drug Interactions
  2. Drug Interactions of Clinical Importance among the Opioids, Methadone and Buprenorphine
  3. Drugs and Conditions That Impact On the Action of Methadone


MethadoneGenetic Implications

  1. Methadone and 2B6 overdose risk
  2. Role_of_CYP2B6_in_Stereoselective_Human_Methadone.8
  3. Methadone N-demethylation in human liver microsomes – lack of stereoselectivity and involvement of CYP3A4


MethadoneNeurobiology of Analgesia

  1. Opioids and Chronic Neuropathic Pain – 2003
  2. d-Methadone Blocks Morphine Tolerance and N-Methyl-d-Aspartate-Induced Hyperalgesia -1999
  3. Mu Opioids and Their Receptors – Evolution of a Concept – 2013
  4. methadone-antinociception-is-dependent-on-peripheral-opioid-receptors-2008
  5. Characterization of methadone as a b-arrestin-biased k-opioid receptor agonist – 2016


MethadoneSleep Apnea

  1. Methadone Used for Pain Linked to Sleep Apnea
  2. APS Sleep Apnea Methadone and Benzodiazepine Therapy


  1. Hyperalgesia in opioid-managed chronic pain and opioid-dependent patients. 2008 – PubMed – NCBI
  2. Opioid induced hyperalgesia – clinical implications for the pain practitioner. – 2009
  3. Opioid-Induced Hyperalgesia – 2012



  1. Methadone tolerance testing in drug misusers – 2006
  2. Opioid tolerance in methadone maintenance treatment – comparison of methadone and levomethadone in long-term treatment – 2016
  3. methadone-reverses-analgesic-tolerance-induced-by-morphine-pretreatment-2015
  4. recovery-from-mu-opioid-receptor-desensitization-following-chronic-treatment-with-morphine-and-methadone-2011
  5. an-opiate-cocktail-that-reduces-morphine-tolerance-and-dependence-2005


MethadoneQTc Prolongation and Cardiac Conduction Disturbances

  1. Methadone, QTc interval prolongation and torsade de pointes
  2. A systematic review of the cardiotoxicity of methadone – 2015

Emphasis on Education


Accurate Clinic promotes patient education as the foundation of it’s medical care. In Dr. Ehlenberger’s integrative ap
proach to patient care, including conventional and complementary and alte
rnative medical (CAM) treatments, he may encourage or provide advice about the use of supplements. However, the specifics of choice of supplement, dosing and duration of treatment should be individualized through discussion with Dr. Ehlenberger. The following information and reference articles are presented to provide the reader with some of the latest research to facilitate evidence-based, informed decisions regarding the use of conventional as well as CAM treatments.


For medical-legal reasons, access to these links is limited to patients enrolled in an Accurate Clinic medical program.


Should you wish more information regarding any of the subjects listed – or not listed –  here, please contact Dr. Ehlenberger. He has literally thousands of published articles to share on hundreds of topics associated with pain management, weight loss, nutrition, addiction recovery and emergency medicine. It would take years for you to read them, as it did him.


For more information, please contact Accurate Clinic.


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