Time to initiate randomized controlled clinical trials with methadone in cancer patients

List of abbreviations

AIDS         Acquired immunodeficiency syndrome

ART          Antiretroviral therapy

CI              Confidence interval

CNS          Central nervous system

HIV           Human immunodeficiency virus

HR            Hazard ratio

MGMT     O6-methylguanin-DNA-methyltransferase

MMT        Methadone maintenance therapy

OR           Opioid rotation

SD            Standard deviation

VA            Veterans Affairs

Background

Since 2017, public media have suggested methadone as a potential cure of cancer. As a result, patients are demanding a prescription of methadone when cancer has been diagnosed or has progressed, perhaps with pain as an excuse. An unrepresentative online survey among German oncologists, conducted in summer 2017, indicated that 83% of 473 responding physicians had experience with patients who “frequently or very frequently” asked for methadone therapy¹. There are indications that an increase in the demand for methadone has spread from Germany to Austria and Switzerland, and beyond^2,3.

It is certainly not in the interest of medical sciences and not of future patients, if today’s patients continue demanding methadone for an unproven therapy. Not surprisingly, several clinical societies have published warning statements on the use of methadone as a cancer therapy^4–7. While all of these societies called for controlled clinical data, they did not evaluate encouraging data on methadone and did not propose designs for a clinical trial. Sometimes, they warned on use of methadone with questionable arguments on its safety. Whether associated to this skepticism or not, no clinical trial evaluating methadone for cancer has yet been initiated, although 152 and 47 trials with methadone as an intervention, but other uses, have been posted on clinicaltrials.gov and in the EU Clinical Trials register, respectively, since 2013⁸. Therefore, this article reviews the all data that could provide a rationale for evaluating methadone as an anticancer agent.

General pharmacological properties of methadone are not discussed here. These properties were discussed in a review proposing methadone as a “tumor theralgesic”. However, it did this without thoroughly discussing the clinical and epidemiologic evidence⁹. It should be stressed that methadone is a racemate and should be understood as such unless therwise indicated. The levo- or (–) form is considered to be active at the µ-opioid receptor, the dextro or (+) form is considered inactive there; other opioid receptors appear to be largely unaffected by both forms¹⁰. In the USA, methadone is licensed for the treatment of moderate to severe pain not responsive to non-narcotic analgesics, for detoxification treatment of opioid addiction, and for maintenance treatment of opioid addiction¹¹. In many European countries, methadone is only approved for the treatment of opioid drug addiction¹². In some European countries, levomethadone is available for the treatment of severe pain and treatment of opioid drug addiction¹³. Dextromethadone has not been approved anywhere, but is currently undergoing a clinical research program major depressive disorder¹⁴.

Preclinical findings

Preclinical data, rather than clinical observations, have triggered research on the use of methadone in cancer. Already in the 1980s, studies on neuroblastoma indicated delayed tumor growth after opioids of the morphine-type and their antagonism by naltrexone^15–17. Similar findings were reported for morphine and naloxone in lung cancer cells, although in concentrations far above the therapeutic range¹⁸. That group then investigated methadone in human lung cancer cells¹⁹. Some effects were observed already at concentrations of 1 nM and strong effects at 10 nM; 10 nM correspond to about 3 ng/mL, i.e. rather below therapeutic plasma levels (see below). They also found similar effects with dextromethadone alone, which was slightly more active than levomethadone in some cell lines. These data prompted further studies by this group confirming the effects of methadone^20–23. Apparently, these findings were not challenged by other groups.

Rather high concentrations of methadone, but not morphine, hydromorphone, or naloxone, increased the accumulation of vinblastine in multidrug resistant cells²⁴.

Interest in the antineoplastic potential of methadone was revived about 10 years later when a German group around Claudia Friesen took up these data²⁵. Her group found that methadone inhibited proliferation of HL-60 myeloid leukemia cells and activated apoptosis pathways. In particular, methadone was able to overcome chemo- and apoptosis resistance, especially but not only resistance to doxorubicin (HL-60 cells were resistant to doxorubicin at a concentration of 100 ng/mL). Methadone alone showed some effects at 15 µM (5000 ng/mL) and was fully effective at 30 µM. Note, however, that peak concentrations of methadone after oral administration in humans were found between 124 to 1255 ng/mL, and steady state levels between 65 to 630 ng/mL¹¹. Hence, the effects in these cell lines might be insufficient for claiming antineoplastic effects of methadone alone under therapeutic conditions.

Then a Spanish group found that methadone was able to induce a necrotic-like cell death in SH-SY5Y cells, i.e. a cell line commonly used in basic research on neuronal functions and cancer²⁶. Although this group admitted to having observed these effects in supratherapeutic doses, they concluded that their finding could explain the toxic effects on various cell lines including cancer and leukemia cells. A Canadian group found methadone to induce apoptosis in pediatric acute lymphoblastic leukemia cells²⁷. They determined high levels for IC₅₀ for all but only one pro-B-cell leukemia cell line that exhibited an IC₅₀ of “only” 9400 ng/mL, i.e. still clearly above the therapeutic range.

In 2008, the German group filed a patent application that claimed, among others things, that methadone (1000 ng/mL) could enhance the apoptotic effects of doxorubicin (100 ng/mL) in glioblastoma cells²⁸. Corresponding details were published 2013 showing that methadone at a concentration as low as 100 ng/mL was able to enhance the apoptotic effects of doxorubicin in concentrations between 10 and 60 ng/mL in acute lymphoblastic leukemia cells²⁹. Peak plasma concentrations of doxorubicin average 4100 ng/mL (SD 220) after a modest 10 mg/m² dose³⁰. Thus, this apoptosis-enhancing combinatorial effect might occur in the therapeutic range of both substances. The authors explained the interaction by increased cellular uptake of doxorubicin by methadone, which in turn might be explained by a down-regulation of cAMP by the opioid²⁹. This group then investigated this interaction in glioblastoma cell lines and confirmed previous findings on apoptosis and doxorubicin enhancement³¹. In this setting methadone exhibited significant effects at 1000 ng/mL or higher.

Thereafter, public interest grew, fueled by public media; the above-mentioned critical statements from oncologic societies were published, and methadone was investigated by other groups. Levomethadone was found to be ineffective in glioblastoma cells; however, data on the racemate were not reported by that group³². Instead of doxorubicin they used temozolomide, an alkylating agent that is recommended for glioblastoma, in contrast to doxorubicin, which is unable to cross the blood-brain barrier, and therefore not recommended for glioblastoma³⁰. In fact, no controlled clinical trial of doxorubicin in glioma has ever been published. Conversely, it is unclear whether temozolomide as such is useful in vitro, as it is active only after conversion to 5-(3-methyltriazen-1-yl)-imidazole-4-carboxamide (MTIC)³³. Another group also found no interaction of methadone and temozolomide in glioblastoma cell lines and methadone being active in only one cell line at a high concentration of 15 000 ng/mL³⁴.

While methadone alone was inactive in melanoma cell lines from a biobank, its combination with cisplatin decreased viability in a cell line displaying a high expression of OPRM1, a main receptor for methadone³⁵. However, cell lines expressing OPRM1 were rather rare in this biobank of melanoma cells.

A very recent report again denied in vitro interaction between methadone and temozolomide in glioblastoma cells, but reported decreased viability of fibroblasts after 1 µM methadone, i.e. about 300 ng/mL³⁶.

A more detailed review on preclinical research findings on antineoplastic effects of methadone was published end of 2018³.

Epidemiological data

From the plethora of epidemiologic studies with methadone, those with data on mortality were selected.

Data from clinical trials

Cochrane reviews on methadone in noncancer pain⁴⁴ and cancer pain⁴⁵ are available. Both meta-analyses were hampered by low to very low quality of the source studies. The review in noncancer pain assessed the quantity and quality of evidence as too poor to draw conclusions on efficacy or safety between methadone, placebo, other opioids, or other treatments⁴⁴. The more recent review in cancer pain concluded that methadone has similar analgesic benefits when compared with morphine, is cheaper in many countries, but might be more difficult to handle than morphine or transdermal fentanyl⁴⁵. They found no differences in safety or mortality. A recent overview on several Cochrane reviews confirmed these statements⁴⁶.

Targeted investigations

The following articles explicitly referred to one of Friesen’s articles^25,29,31.

Discussion of evidence

The preclinical data suggests that racemic methadone itself can inhibit the growth of human lung cancer cells¹⁹, increase the uptake of doxorubicin into leukemia cells²⁹, and reduce viability of fibroblasts³⁶ at concentrations that could be achieved with normal doses. There is little rationale to consider glioma or other CNS cancers as useful indication of methadone or add-on treatment with doxorubicin.

Epidemiological data are encouraging, most of all the VA study³⁷. The four-cohort study³⁹ numerically supports the findings of the VA study, as well as the opioid rotation study⁴⁸. The study investigating out-of-hospital mortality⁴⁰ should not be considered contradictory due to selective counting of deaths and the focus on noncancer pain. The positive outcomes of HIV studies^42,43 might be explained by both the beneficial effects on cancer and a diminished use of illicit drugs. However, use of illicit drugs had no relevant quantity in the other studies.

The two targeted investigations were too small, but were also compatible with beneficial effects^47,48.

All in all, epidemiologic and clinical data consistently indicate that patients treated with methadone had a better prognosis than those treated with morphine, and that this difference was larger the higher the proportion of patients with cancer diagnosis was.

What could alternative explanations be? Is methadone simply safer than long-acting morphine? Other evidence⁴⁹, guidelines^50,51, and market data⁵² on opioids do currently not support this assumption. Furthermore, there is no pharmacologic or physiologic rationale explaining why such safety advantage could be confined to unselected cancer patients.

Or was there a hidden selection bias? In fact, the VA study³⁷ did not control for socioeconomic status. However, it would be counterintuitive to assume that the “cheaper” methadone would be more often prescribed to the “rich” and the “more natural” morphine rather to the “poor”.

A reasonable explanation is that methadone yields protective or beneficial effects in cancer. And this effect cannot be explained by an effect of methadone in glioma or other central nervous cancers, as these cancers have too low a prevalence.

What should be done?

If methadone is beneficial, whether alone or with doxorubicin, these effects may not be so overwhelming that historically controlled or other cohort studies would be sufficient to demonstrate efficacy. Any uncontrolled distribution of methadone is certainly inappropriate and should not be encouraged. Even prospective registry studies do not appear to be reasonable solutions, as enormous sample sizes would be required given the extreme variability of indications and cancer therapies and the assumed moderate effects. Moreover, prospective registry studies could hamper recruitment into properly designed clinical trials.

As patients will continue demanding methadone for cancer, it is now time to initiate randomized controlled clinical trials with methadone in cancer patients. Doxorubicin could be used in a 2x2 design or as a factor in the analysis, calling for patients eligible for doxorubicin therapy. Instead, cancer pain should be no selection criterion. The control group could be placebo; however, a reasonable alternative could be watchful waiting for, say, 6 months. This is because most “active” patients and some investigators might correctly guess the true nature of blinded treatment. Moreover, open designs would facilitate treatment of breakthrough pain, maybe with other opioids. Anyhow, the focus should be on opioid-naïve patients.

The dosage of methadone could be based on the paper by Onken et al.⁴⁷. A dose or concentration controlled design could be considered⁵³. To investigate opioid-experienced patients, a randomized withdrawal design⁵⁴ might be an option, initially switching all patients to methadone and then withdrawing (or not) it in a blinded manner after, say, 2 weeks. Under such circumstances, it would be unwise to administer any chemotherapy before the end of the withdrawal phase.

Under these prerequisites, methadone appears to be sufficiently safe for initiating a large trial. It should be stressed that it is unclear as to whether methadone would “win” against control. However, almost any outcome would relevantly expand medical knowledge and provide appropriate arguments for answering patients’ hopes, whether justified or not.

Conclusions

Data availability

No data are associated with this article.