Methadone for Cancer Pain

Dr. Weeks’ Comment: Would you throw a lead lifejacket to a drowning man?

I hope not.

Would you recommend an immunosuppressive pain medication to a person dying of the immune disorder commonly referred to as “cancer”?  

I hope not. 

However, doing just that is  the standard of care?  

Here is the bizarre fact:     Opiates, which suppress immune function in humans,  are the primary pain medication used for cancer pain and while helping pain, this medication weaken the life support system called your immune system.  Palliative care (“comfort care”) is one thing, but if you want to live and have not given up, ask your oncologist to give you a different medication for your pain such as, perhaps, methadone which acts like opiates except for 3 things: 1) methadone doesn’t lessen the immune function; 2) methadone is not damaging to the liver;  3) methadone has been shown to  inhibit cancer cells…  “significantly inhibit the in vitro and in vivo growth of human lung cancer cells”.   Curious?  Search the internet for  “methadone” and “opiate” and “immune function”.


Twelve Reasons for Considering Buprenorphine as a Frontline Analgesic in the Management of Pain.

Davis MP.

J Support Oncol. 2012 Jul 16. [Epub ahead of print]

Buprenorphine is an opioid that has a complex and unique pharmacology which provides some advantages over other potent mu agonists. We review 12 reasons for considering buprenorphine as a frontline analgesic for moderate to severe pain:     (1) Buprenorphine is effective in cancer pain;     (2) buprenorphine is effective in treating neuropathic pain; (3) buprenorphine treats a broader array of pain phenotypes than do certain potent mu agonists, is associated with less analgesic tolerance, and can be combined with other mu agonists;    (4) buprenorphine produces less constipation than do certain other potent mu agonists, and does not adversely affect the sphincter of Oddi;     (5) buprenorphine has a ceiling effect on respiratory depression but not analgesia;     (6) buprenorphine causes less cognitive impairment than do certain other opioids;      (7) buprenorphine is not immunosuppressive like morphine and fentanyl;     (8) buprenorphine does not adversely affect the hypothalamic-pituitary-adrenal axis or cause hypogonadism;     (9) buprenorphine does not significantly prolong the QTc interval, and is associated with less sudden death than is methadone;      (10) buprenorphine is a safe and effective analgesic for the elderly;       (11) buprenorphine is one of the safest opioids to use in patients in renal failure and those on dialysis; and       (12)withdrawal symptoms are milder and drug dependence is less with buprenorphine. In light of evidence for efficacy, safety, versatility, and cost, buprenorphine should be considered as a first-line analgesic.



Methadone HIV Infection and Immune Function  by Herman Joseph


….Many physicians or medical professionals incorrectly believe that methadone inhibits the immune system and functioning. While this is true of all opioids, and especially the short acting opiates it is not true of methadone. And in fact, methadone is the only opioid that does not inhibit the immune system or functioning. This is an important characteristic of methadone when considering its impact on HIV+ methadone patients. But methadone does not only not inhibit the immune system-it restores immune functioning.

The potential for normalization of endocrine and immune functioning is especially crucial when treating HIV positive methadone patients. The evidence of immune restoration from HIV negative methadone patients hints that there may be a partial restoration of immune functioning for HIV positive methadone patients (Kreek, 1988). While this is not proven, there are many other advantages for HIV positive heroin users to be placed and maintained on methadone.

In Switzerland a three-year prospective study followed a group of HIV-infected methadone maintenance patients and a contrast group of HIV-infected heroin users who did not enter methadone maintenance treatment (Weber, Ledergerber, Opravil & Luthy, 1990). The results showed that a significantly lower proportion ofmethadone maintenance patients progressed to AIDS as compared with the untreated heroin users, 24 percent versus 41 percent, almost a-2 fold increase within the period of the study.

Methadone when prescribed as a maintenance medication functions as a normalizer for a deranged physiology and not as a mood altering narcotic substitute (Dole, Nyswander & Kreek, 1966; Joseph & Dole, 1970). Methadone maintenance, is therefore corrective but not curative….




The effects of methadone on immune function among injecting drug users: a review



Methadone maintenance therapy is advocated as a major preventive strategy for the spread of the human immunodeficiency virus (HIV) and other blood-borne infectious agents among injecting drug users (IDUs) because of its effects in decreasing the frequency of injecting and presumably sharing of equipment. As an opioid agonist, methadone may share the direct and indirect immunoregulatory effects of other opioids, and thus affect susceptibility to, and the natural history of, HIV infection. Available evidence pertaining to methadone and immune function is reviewed. The long-term immunosuppression observed in heroin injectors on present (incomplete) evidence appears to be caused by factors associated with a drug-using lifestyle rather than by a direct action of heroin. Although data are conflicting, it is most likely that methadone does not significantly impair immune function and is safe for HIV-infected IDUs, possibly even allowing some improvement of immune function to occur. The increasing reliance placed on methadone maintenance to control the epidemic of HIV infection in IDUs requires that remaining uncertainties regarding methadone and immune function are clarified urgently.




Methadone is Safe for Liver

Since the start of using methadone to treat patients with addiction, suspicion has circulated that the methadone-maintenance treatment would cause damage to various internal organs, including the liver. However, the commonly used daily oral doses of methadone for the purpose of preventing withdrawal symptoms are safe. Methadone has been shown to be nontoxic to the liver, according to a study led by D.M. Novick, published in “Alcoholism: Clinical and Experimental Research.” Reported side effects include sweating, constipation, sexual dysfunction and sleep irregularities. These side effects are mild and transient, often disappearing without medical




Nonconventional opioid binding sites mediate growth inhibitory effects of methadone on human lung cancer cells

Author: R Maneckjee and J D Minna  National Cancer Institute-Navy Medical Oncology Branch, National Cancer Institute, Bethesda, MD 20889.



Methadone was found to significantly inhibit the in vitro and in vivo growth of human lung cancer cells. The in vitro growth inhibition (occurring at 1-100 nM methadone) was associated with changes in cell morphology and viability detectable within 1 hr and was irreversible after a 24-hr exposure to the drug. These effects of methadone could be reversed in the first 6 hr by naltrexone, actinomycin D, and cycloheximide, suggesting involvement of opioid-like receptors and the requirement for de novo mRNA and protein synthesis. The inhibitory effects of methadone on the growth of lung cancer cells also could be achieved by the less addictive (+) isomer of methadone. Characterization of the methadone binding to lung cancer cell membranes revealed high-affinity (nM), saturable binding sites for (+/-)-[3H]methadone, which cross-reacted with ligands for kappa, phencyclidine, sigma, but not mu, and delta opioid receptors, and the binding characteristics appeared to be different from methadone sites present in rat brain. Methadone decreases cAMP levels in lung cancer cells, but the receptors are not coupled to a pertussis toxin-sensitive guanine nucleotide-binding regulatory protein. We conclude that the lung cancer growth inhibitory effects of methadone are significant, occur at low concentrations, and are mediated by a nonconventional type of opioid binding site distinct from methadone receptors found in the brain.



Pain Ther.2019 May 17. doi: 10.1007/s40122-019-0126-0.

Pain Control in Latin America: The Optimized Role of Buprenorphine in the Treatment of Cancer and Noncancer Pain.

Pergolizzi JV Jr1, Taylor R Jr1, LeQuang JA2, Lara A3, Ortiz AH3, Iban MAR4.



Pain is a terrible health problem that transcends borders and nationalities, although there may be significant differences among regions regarding pain management. In Latin America (LatAm, composed of the many nations of Central America, South America, Mexico, and the Caribbean), access to healthcare, pain management, and opioid analgesics can vary. Despite an international U.S.-led trend toward greater control in opioid prescribing, the role of opioids in the management of severe pain in LatAm is probably smaller than it should be, as opioid consumption in LatAm overall is low. Buprenorphine is a strong opioidwith certain characteristics that make it a potentially useful analgesic agent in LatAm: it has a unique pharmacology that allows for transdermal administration and a favorable safety profile with a ceiling effect for respiratory depression. It has a well-studied low risk potential for misuse, and there is strong evidence for its safety and efficacy in managing both cancer and noncancer pain in adults. Caregivers and policy makers in LatAm may learn from the U.S. experience with opioids in order to develop protocols to better and safely manage pain, and it is possible that buprenorphine will play a key role.



Pain Res Treat.2018 Oct 15;2018:8610538. doi: 10.1155/2018/8610538. eCollection 2018.

Differences between Transdermal Fentanyl and Buprenorphine in the Elderly Hospice Patients.

Golčić M1, Dobrila-Dintinjana R1, Golčić G1, Gović-Golčić L2.




Opioids are the most important drugs in treating pain in palliative care patients. Transdermal formulations are especially useful due to their noninvasive nature and minimal interference in daily life. However, studies have shown a controversial relationship of opioids to survival and a rise in deaths associated with the use of transdermal opioids. Although applying precise doses is paramount, we have no clear recommendations for the exact equianalgesic ratio for buprenorphine patch and no recommendation for the type of transdermal opioid to use in hospice.



A total of 292 patients (75.8%) used fentanyl patch and 93 (24.1%) were on buprenorphine patch. Patients had virtually the same characteristics in both groups. However, when using a 1:100 buprenorphine equianalgesic ratio, there were significant differences in initial and final doses, and it seems that a 1:80 conversion rate is more accurate for elderly hospice patients. Finally, there was no difference in survival between the two groups using transdermal opioids, with or without adjuvant analgesics.


There were no differences in survival between the group using transdermal fentanyl and the group using buprenorphine in the elderly hospice population. Although adjuvant NSAIDs could be useful in the treatment of pain in terminal cancer, they do not affect survival or reduce the opioid doses, while a 1:80 equianalgesic ratio of buprenorphine might be the most appropriate in this population.

PMID: 30410797 PMCID: PMC6205095DOI: 10.1155/2018/8610538

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Indian J Palliat Care.2018 Oct-Dec;24(4):500-504. doi: 10.4103/IJPC.IJPC_83_18.

A Comparative Study of Transdermal Buprenorphine and Oral Morphine in the Treatment of Chronic Pain of Malignant Origin.

Choudhury K1, Dasgupta P1, Paul N1, Choudhury KB1, Roy B1, Maity S1.




The study was designed to compare the efficacy and adverse effects of buprenorphine transdermal (TD) against oral morphine in pain management of cancer patient.


63 patients were analyzed. Commonest primary cancers were breast in females and head and neck in male individuals in both arms. Initial VAS score of arm A and arm B were 81.25 and 82.26 respectively. By 1st week, 11 arm A patients were relieved from pain. Another 17 patients of arm A became pain free by 2nd week, total dose of 40 μg/h. Only 4 patients needed 60 μg/h for pain relief. In arm B, 2 patients were relieved by 1 week with total 30mg/day morphine, 11patients were relieved with 60 mg/day by 2nd week and 12 patients with 90 mg/day. 6 patients were relieved with 120 mg/day dose at the end of 4thweek. Nausea and constipation were stastically higher in Arm B compared to that of Arm-A.


TD Buprenorphine had similar efficacy with oral morphine, with better toxicity profile and better compliance.

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Drugs.2018 Aug;78(12):1211-1228. doi: 10.1007/s40265-018-0953-z.

Treating Chronic Pain: An Overview of Clinical Studies Centered on the Buprenorphine Option.

Davis MP1, Pasternak G2, Behm B3.



The buprenorphine receptor binding profile is unique in that it binds to all three major opioid receptors (mu, kappa, delta), and also binds to the orphan-like receptor, the receptor for orphanin FQ/nociceptin, with lower affinity. Within the mu receptor group, buprenorphine analgesia in rodents is dependent on the recently discovered arylepoxamide receptor target in brain, which involves a truncated 6-transmembrane mu receptor gene protein, distinguishing itself from morphine and most other mu opioids. Although originally designed as an analgesic, buprenorphine has mainly been used for opioid maintenance therapy and only now is increasingly recognized as an effective analgesic with an improved therapeutic index relative to certain potent opioids. Albeit a second-, third-, or fourth-line analgesic, buprenorphine is a reasonable choice in certain clinical situations. Transdermal patches and buccal film formulations are now commercially available as analgesics. This review discusses buprenorphine pharmacodynamics and pharmacokinetics, use in certain populations, and provides a synopsis of systematic reviews and randomized analgesic trials. We briefly discuss postoperative management in patients receiving buprenorphine maintenance therapy, opioid equivalence to buprenorphine, rotations to buprenorphine from other opioids, and clinical relevance of buprenorphine-related QTc interval changes.


Scand J Pain.2013 Jul 1;4(3):148-152. doi: 10.1016/j.sjpain.2013.05.004.

Buprenorphine-Clinically useful but often misunderstood.

Butler S1.



Background There are a number of false myths about buprenorphine based on unconfirmed animal data, even from isolated animal organs, and early clinical research. These myths came into textbooks on pharmacology and pain about 30 years ago and have been difficult to eradicate. Animal models of pain and pain relief are notoriously unreliable as predictors of human clinical effects. The fact is that in clinical practice there is NO bell-shaped dose-response curve, there is NO plateau on the dose-response curve, and there is NO antagonist effect from buprenorphine on other mu-opioid agonists. Methods This narrative, topical review of relevant research publications evaluates new knowledge on the pharmacodynamics and pharmacokinetics of buprenorphine of importance in clinical practice. Results Buprenorphine is a potent opioid analgesic acting on all four opioid receptors: it is an agonist on the mu-, the delta, and the ORL-1 receptors. It is an antagonist at the kappa-receptor. Buprenorphine has a number of active metabolites with different effects on the four opioid receptors; all except the norbup-3-glu are analgesic. Buprenorphine itself is not a respiratory depressant or sedative, but some of its active metabolites are. Buprenorphine and its active metabolites are not excreted by the kidney. Therefore buprenorphine may be used in patients with advanced renal failure. Buprenorphine has a slow onset and a long offset. These properties are advantageous, except sometimes when treating severe acute pain. Its agonist effect on the ORL-1 receptor reduces reward-effects and slows the development of tolerance to the analgesic effects. Buprenorphine inhibits voltage-gated sodium-channels and enhances and prolongs peripheral nerve blocks. Its ORL-1 -effect at the spinal cord may do the same. Buprenorphine is well suited for treatment of chronic pain, especially chronic neuropathic pain and cancer pain. The beneficial effects as a co-medication during treatment of the opioid-abuse disease are due to its slow onset (less “kick-effect”). Its prolonged offset-time reduces the likelihood of acute withdrawal problems and reduces the “craving” of opioids. Adverse effects Buprenorphine, being a mu-agonist, may induce or maintain opioid addiction. Illegally obtained high-dose transmucosal buprenorphine, intended for treatment of addiction, is dissolved and injected by opioid abusers. This is an increasing problem in some countries. Conclusions Buprenorphine’s unusual pharmacodynamics and pharmacokinetics make it an ideal opioid for treatment of most chronic pain conditions where opioid therapy is indicated. Implications Buprenorphine is a well studied and often misunderstood analgesic opioid drug. The evidence base predicts that it will be an increasingly important alternative for treatment of chronic pain conditions caused by cancer and non-cancer diseases. It will continue to be an attractive alternative to methadone for opioid abuse rehabilitation.



Dtsch Arztebl Int.2018 Mar 2;115(9):135-142. doi: 10.3238/arztebl.2018.0135.

Opioid Rotation in Cancer Pain Treatment.

Schuster M1, Bayer O, Heid F, Laufenberg-Feldmann R.




Rotating several different WHO level III opioid drugs is a therapeutic option for patients with chronic cancer-related pain who suffer from inadequate analgesia and/or intolerable side effects. The evidence favoring opioid rotation is controversial, and the current guidelines in Germany and other countries contain only weak recommendations for it.


This review is based on pertinent publications retrieved by a systematic review of the literature on opioid rotation for adult patients with chronic cancerrelated pain who are regularly taking WHO level III opioids by the oral or trans – dermal route.


9 individual studies involving a total of 725 patients were included in the analysis, and 3 previous systematic reviews of studies involving a total of 2296 patients were also analyzed. Morphine, oxycodone, fentanyl, hydromorphone, and buprenorphine were used as first-line opioid drugs, and hydromorphone, bupre – norphine, tapentadol, fentanyl, morphine, oxymorphone, and methadone were used as second-line opioid drugs. In all of the studies, pain control was achieved for 14 days after each rotation. In most of them, the dose of the new drug introduced in each rotation needed to be increased above the dose initially calculated from a rotation ratio, with the exception of rotations to methadone. The frequency of side effects was only rarely lessened, but patients largely considered the result of opioid rotation to be positive. No particular opioid drug was found to be best.


Opioid rotation can improve analgesia and patient satisfaction. The success of opioid rotation appears to depend on the magnitude of the initial dose, among other factors. Tables of equianalgesic doses should be considered no more than a rough guide for determining the dose of the new drug. Rotations to methadone should be carried out under clinical supervision in experienced hands.

PMID: 29563006 PMCID: PMC5876542DOI: 10.3238/arztebl.2018.0135

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