Downloaded from pmj.bmj.

com on 20 February 2008

Methadone: applied pharmacology and use as

adjunctive treatment in chronic pain
R Brown, C Kraus, M Fleming and S Reddy

Postgrad. Med. J. 2004;80;654-659

doi:10.1136/pgmj.2004.022988

Updated information and services can be found at:

http://pmj.bmj.com/cgi/content/full/80/949/654

These include:
References This article cites 51 articles, 12 of which can be accessed free at:
http://pmj.bmj.com/cgi/content/full/80/949/654#BIBL

4 online articles that cite this article can be accessed at:

http://pmj.bmj.com/cgi/content/full/80/949/654#otherarticles
Rapid responses You can respond to this article at:
http://pmj.bmj.com/cgi/eletter-submit/80/949/654

Email alerting Receive free email alerts when new articles cite this article - sign up in the box at the
service top right corner of the article

Topic collections Articles on similar topics can be found in the following collections

Pharmacology and toxicology (381 articles)

Palliative Medicine (154 articles)

Notes

To order reprints of this article go to:

http://journals.bmj.com/cgi/reprintform
To subscribe to Postgraduate Medical Journal go to:
http://journals.bmj.com/subscriptions/
 Downloaded from pmj.bmj.com on 20 February 2008
654

REVIEW

Methadone: applied pharmacology and use as adjunctive

treatment in chronic pain
R Brown, C Kraus, M Fleming, S Reddy
...............................................................................................................................

Postgrad Med J 2004;80:654–659. doi: 10.1136/pgmj.2004.022988

This article reviews the unique pharmacological properties withdrawal. We then focus upon an approach
to the prescription of methadone for the treat-
of methadone and outlines its appropriate clinical ment of chronic pain conditions. Finally, we
application, with focus upon its use in the treatment of discuss the adverse effects of and potential drug
chronic pain. Although methadone is most widely known interactions with methadone which may occur
with usual clinical use.
for its use in the treatment of opioid dependence,
methadone also provides effective analgesia. Patients who PHARMACOLOGY
experience inadequate pain relief or intolerable side effects Methadone occurs in R-enantomeric and S-
with other opioids or who suffer from neuropathic pain enantomeric forms, with essentially all of its
activity due to activity of R-methadone.15
may benefit from a transition to methadone as their Methadone exerts its activity through binding
analgesic agent. Adverse effects, particularly respiratory to and activating m opioid receptors centrally and
depression and death, make a fundamental knowledge of in the periphery. This activity produces the
effects common to all m opioid agonists: analge-
methadone’s pharmacological properties essential to the sia, euphoria, constipation, sedation, respiratory
provider considering methadone as analgesic therapy for depression, nausea, and miosis. Additionally,
a patient with chronic pain. methadone antagonises N-methyl-D-aspartate
receptors, which may increase its effectiveness
...........................................................................
in the treatment of neuropathic pain compared
with other opioids.16

M
ethadone is a synthetic opioid medication
best known for its use in the treatment of Pharmacokinetics
opioid dependence. Methadone is also an Methadone is a fat soluble drug which is rapidly
effective analgesic agent, potentially with absorbed after oral administration. Time to peak
increased efficacy in the setting of neuropathic concentration, however, varies from one to five
pain.1–3 Patients experiencing inadequate analge- hours. Methadone induced slowing of gastric
sia or adverse effects while on other opioids may emptying may account for longer time to peak
also benefit from a transition to methadone.1–11 concentration in chronic users. Oral bioavail-
Additionally, unique pharmacological properties ability of tablets is approximately 60%–70%, but
make methadone a useful addition to the care wide variation among patients exists.15 The
provider’s arsenal of prescription analgesic analgesic effect of a dose begins within 30 to
agents. 60 minutes after administration and generally
Methadone’s excellent oral bioavailability and lasts for four to six hours.3
mucosal absorption, effectiveness as an analgesic Methadone is highly bound to plasma pro-
agent, low cost, long half life, and availability in teins. In particular, a1-acid glycoprotein is
oral, parenteral, and suppository forms make it important, because disease states, like cancer,
an excellent alternative for the treatment of both may induce a rise in the concentration of this
cancer and non-cancer pain.8 Medication inter- protein and, as a result, affect the concentra-
actions and the potential for serious adverse tion of free methadone.15 Certain drugs may
effects (particularly central apnoea and death, influence a1-acid glycoprotein concentrations
which have received recent attention in the and, in turn, methadone concentrations.
popular press)12–14 make an understanding of Methadone may be displaced from plasma
methadone’s pharmacological profile essential to proteins by drugs like propranolol, certain
See end of article for the prescribing provider. phenothiazines, and imipramine. Other drugs
authors’ affiliations Many individuals participating in methadone may decrease plasma protein and, theoretically,
.......................
maintenance treatment for opioid dependence increase free methadone levels. Examples of
Correspondence to: seek medical care in the community outside of such drugs are carmustine and mechloretha-
Dr Randall Brown, their addiction treatment facility. An under- mine. Finally, drugs may also selectively compete
University of Wisconsin
Department of Family
standing of potential adverse effects and medica- for protein binding sites, resulting in situations
Medicine, 777 S Mills St, tion interactions is important when caring for where their own free levels might increase. The
Madison, WI 53715, USA; this population as well, so that the provider can tricylic antidepressants, progesterone, and lido-
[email protected]. avert untoward events resulting from medication caine are a few examples. Although animal data
edu interactions. suggest that dose adjustments based on protein
Submitted 14 April 2004 In this article, we discuss the pharmacology binding may be necessary, there are no data in
Accepted 10 May 2004 of methadone and briefly comment upon its use humans to suggest these interactions are clini-
....................... in the treatment of opioid dependence and cally significant.17

www.postgradmedj.com
 Downloaded from pmj.bmj.com on 20 February 2008
Methadone and chronic pain 655

Methadone is also widely distributed to tissue, and, with effects (constipation, euphoria, nausea/vomiting) or inade-
continuous use, tissue levels may exceed levels in plasma. quate analgesia with other prescribed opioids may benefit
This extensive protein and tissue binding is responsible for from a transition to methadone.5 7 Additionally, methadone
the long plasma half life of the drug, particularly with often provides analgesia superior to other opioids in the
continuous use.9 setting of neuropathic pain syndromes.3 Furthermore, a
Metabolism of methadone to inactive forms is the principle reduced level of tolerance to analgesic effects and less
means of elimination.15 Less than 10% of an oral dose is constipation has been reported for methadone as opposed
extracted by the liver during first pass.9 The drug is to other opioids.6
metabolised both by the liver and by intestinal CYP 3A4 Given the short duration of analgesia (4–6 hours) relative
and, to a lesser extent, by CYP 2D6. Some of the variability of to methadone’s half life, the use of methadone as an
enzyme activity in different people likely accounts for the analgesic agent requires a more frequent dosing regimen
large differences in clearance and half life of methadone seen than the daily dosing used for the treatment of opioid
within a population.15 For example, due to a polymorph of dependence. Usual analgesic treatment regimens with
CYP 2D6, a subset of the white population, less than 10%, are methadone require dosing every eight to 12 hours. The long
considered to be poor metabolisers of methadone.18 Estimates half life of methadone in the setting of more frequent dosing
of methadone half life vary from 15 to 55 hours. In addition creates the potential for drug accumulation and adverse
to metabolic inactivation, parent drug and metabolites are effects. Many protocols for a transition to methadone from
also eliminated in the faeces and urine.15 other opioid analgesics have been put forward in the
Age does not appear to have a large influence on clearance literature.1 2 4 29 30 These methods are of two basic types: (1)
and generally no change in dose is required for persons over a rapid transition in which the previously prescribed opioid is
age 65 years. For patients with impaired renal function, completely discontinued with institution of methadone
methadone clearance via faeces will increase and no dose analgesic therapy, and (2) a slow transition in which the
adjustment is necessary. For patients with end stage renal previously prescribed opioid is tapered in conjunction with
disease, some experts suggest a 50% reduction in methadone titration of methadone dosing. Equianalgesic doses of the
dosing. Because methadone is highly protein bound, little is most commonly prescribed opioids are provided in table 1.
expected to be removed from the plasma with dialysis. Boxes 1 and 2 provide examples of each protocol (slow and
Patients with chronic, stable liver diseases may be able to rapid) for transition to methadone using morphine milligram
tolerate usual methadone maintenance doses. For patients equivalents.
with acute hepatitis and elevated liver enzymes, higher doses Though not generally a first line agent, methadone may be
of methadone may be required.15 19 considered early on in the treatment of neuropathic pain and/
No relationship has been established between plasma or in situations where cost issues are compelling. This
concentration and analgesic effect.9 For the treatment of situation mandates caution because, in the opioid naı̈ve
chronic pain, treatment should be titrated to clinical effect patient, methadone may precipitate respiratory arrest. A
rather than a drug level.3 history of sleep apnoea, severe asthma or respiratory failure,
right heart failure, morbid obesity, or the concurrent use or
CLINICAL APPLICATIONS abuse of sedative drugs (for example, alcohol, muscle
Methadone for opioid dependence relaxants) increase the risk of respiratory depression or arrest
Since the enactment of the Narcotic Addicts Treatment Act in with methadone. The first visit with the care provider should,
1973, methadone prescription in the United States for opioid therefore, include a detailed medical history to screen for
dependence or opioid withdrawal has been (and continues to these high risk situations. A methadone regimen for chronic
be) legal only in the setting of a federally licensed methadone pain in the opioid naı̈ve patient may then begin with a low
maintenance facility.20 Resources for the care of health issues dose (5 mg or less twice daily) and be gradually (an
unrelated to substance abuse are often limited in these additional 5 mg daily every 72 hours) titrated upward to
facilities. Methadone maintained individuals, therefore, pain relief. Total daily doses exceeding 120 mg are rarely
frequently seek medical care from community providers. required to provide adequate 24 hour analgesia.1 As needed
Over 150 000 opioid dependent individuals are enrolled in doses of short acting analgesics, such as oxycodone, hydro-
methadone treatment centres in the United States. The codone, or short acting morphine preparations, may be
United States Office of National Drug Control Policy considered for the treatment of breakthrough pain.
estimates that these services reach one in 10 to one in eight An optimal concentration of methadone for maintenance
actively opioid dependent individuals in the United States.21 therapy for opioid dependence is considered to be 400 mg/l,
Methadone maintenance treatment has been shown to although in some studies, designed to determine an effective
decrease use of heroin and other drugs; reduce the acquisi- concentration, a threshold was not found. On the other hand,
tion and transmission of HIV,22 23 hepatitis B, and hepatitis some patients will have a reasonable clinical response with
C24; reduce criminal behaviour25; and has been shown to be a lower serum concentrations and other factors such as
cost effective treatment for opioid dependence.26 Most of the receptor sensitivity, social support, and psychological issues
benefits of methadone maintenance have been shown to be may also play a part. Therefore, therapeutic drug monitoring
related to methadone dose and to duration of treat-
ment.20 27 28 Table 1 Opiate milligram equivalents*
Drug Equianalgesic doses
Methadone for chronic pain
Federal and state regulations restricting the use of metha- Codeine 180–200 mg
done in the setting of opioid dependence and withdrawal to Fentanyl 25 mg transdermal
specially licensed facilities do not apply to the prescription of Hydrocodone 30 mg
Morphine 30–60 mg oral
methadone for chronic pain. Therefore, the care provider may Oxycodone 30 mg
consider the use of methadone as an analgesic agent for the
treatment of chronic pain. *Methadone conversion is not included due to varying
In addition to being effective treatment for opioid conversion ratios at varying prior doses of other opiates. See
boxes 1 and 2 for appropriate conversion to methadone
dependence, methadone provides effective analgesia with based upon morphine milligram equivalents.
several unique properties. Patients experiencing adverse

www.postgradmedj.com
 Downloaded from pmj.bmj.com on 20 February 2008
656 Brown, Kraus, Fleming, et al

Box 1: United Kingdom model for switching from Box 2: Edmonton model for switching from
morphine to methadone (rapid transition) 1 morphine to methadone (slow transition) 2

N The use of the previous opiate is stopped and replaced N Day 1: Decrease morphine dose by 30% and replace
by a fixed dose of methadone. A patient who was with oral or rectal methadone every eight hours using
receiving 300 mg or less of morphine milligram titration equianalgesic morphine-to-methadone dose
equivalents daily would have the dose replaced at a ratio of 10:1.
ratio of 10 mg morphine: 1 mg methadone. A patient
receiving greater than 300 mg of morphine milligram
N Day 2: If pain control is adequate, decrease the
original dose of morphine by another 30%. Increase
equivalents daily would receive a fixed dose of 30 mg the dose of methadone only if the patient experiences
methadone. This dose is then used at intervals of not moderate to severe pain. Treat transient pain with
less than three hours as needed for analgesia. rescue doses of short acting opioids.
N On day 6, the amount of methadone administered over N Day 3: Discontinue the last 40% of the original
the previous two days is converted to a regimen morphine dose and maintain the patient on regular
delivered regularly at 12 hour intervals. methadone administered every eight hours plus about
N Methadone requirements should be expected to 10% of the daily methadone dose administered as a
decrease during days 2 and 3 and reach steady state rescue dose for breakthrough pain.
on days 4–5.

taper generally should not exceed 1 mg/day.31 A 5 mg/week

is not recommended routinely for all patients receiving taper is convenient given methadone’s availability in 5 mg
methadone maintenance.15 No relationship has been estab- and 10 mg tablet forms.
lished between plasma concentration and analgesic effect.9 Aching muscles and joints, insomnia, nausea, and mood
For the treatment of chronic pain, therefore, treatment changes may indicate opioid withdrawal.32 If the patient
should be titrated to clinical effect rather than a drug level.3 begins to experience opioid withdrawal effects, symptomatic
treatments on an as-needed basis may assist in the manage-
CESSATION/TAPER OF METHADONE ment of a continued taper if necessary. Clonidine or a b-
Should cessation of methadone treatment be indicated, blocker may alleviate sympathomimetic symptoms (tachy-
gradual tapering will minimise withdrawal symptoms. The cardia, lacrimation, stuffy nose, sweats). These medications

Table 2 Drug interactions associated with enhanced methadone effects

Pharmacokinetic effects Clinical effects Type of evidence Possible mechanism Reference

Antibiotics
Ciprofloxacin Sedation/respiratory Single case report; ciprofloxocin Inhibition of CYP1A2 39
depression/confusion reintroduced with same outcome and/or CYP3A4
Fluconazole 35% q AUC; 27% No signs/symptoms of Randomised, double blind, Inhibition of CYP3A4, 38
q peak, 48% q trough, methadone overdose placebo controlled trial; 13 possibly others
24% Q clearance reported participants received fluconazole
methadone 200 mg/day

Antidepressants
Fluoxetine Some patients had None reported Nine case reports of serum levels Inhibition of CYP2D6 40
moderate q plasma level, of methadone after addition of
but this was less marked fluoxetine; two participants had
than with fluvoxamine also use fluvoxamine previously
in the two patients
Fluvoxamine q serum methadone Hypoxemia, hypercapnia Single case Inhibition of one of 41
level several enzymes:
CYP3A4, CYP1A2,
CYP2C9, CYP2C19
q serum methadone Patient unable to achieve Single case Inhibition of one of 42
level effective methadone level several enzymes:
despite high dose. Had CYP3A4, CYP1A2,
increased methadone level CYP2C9, CYP2C19
with fluvoxamine and
decrease in withdrawal
symptoms
Paroxetine q R-methadone plasma No side effects reported Prospective administration of Inhibition of CYP2D6; 43
levels in eight CYP2D6 by patients and no signs paroxetine in 10 methadone- also possibly CYP1A2,
extensive metabolisers of intoxication were noted using patients (two poor CYP2C9, CYP2C19,
but not in poor metabolisers, eight extensive and CYP3A4
metabolisers metabolisers)
Sertraline q methadone plasma level No significant difference in Prospective, 12 week, Inhibition of several 44
26% with addition side effects between groups randomised, placebo controlled isoenzymes (CYP2D6,
of sertraline trial; 12 patients received up to CYP3A4, CYP1A2,
sertraline 200 mg/day CYP2C9, CYP2C19)

Adapted with permission from Eap CB, Buclin T, Baumann P. Interindividual variability of clinical pharmacokinetics of methadone. Clin Pharmacokinet 2002;
41:1153–93.15
AUC, area under the curve.

www.postgradmedj.com
 Downloaded from pmj.bmj.com on 20 February 2008
Methadone and chronic pain 657

may also alleviate some of the subjective irritability common medication side effects, and may assist the practitioner in the
in opioid withdrawal. Prochlorperazine or promethazine management of these side effects.
assist in the management of nausea and vomiting. Methadone acts upon central opioid receptors, as do the
Loperamide will alleviate diarrhoea. Dicyclomine calms other opioid drugs. This action may reduce hypercapnoeic
abdominal cramping; and a limited supply of a benzodiaze- and hypoxic ventilatory drives resulting in respiratory
pine such as lorazepam, might be considered to assist in the depression. The most severe potential consequence of this
control of insomnia and irritability/anxiety. effect is central apnoea. Many cases of mortality due to this
effect have been reported. In most situations, medication
SIDE EFFECTS OF METHADONE interactions were missed, medical risk factors ignored, or
Familiarity with the side effect profile of methadone will doses increased too quickly.22 Methadone toxicity can also
assist the practitioner in the appropriate titration of a result from inadequately spaced dosage regimens (dosing
methadone regimen, will obviate the unnecessary laboratory more frequently than every eight hours) due to the drug’s
investigation of signs and symptoms known to be common long half life and consequent drug accumulation.17 Careful

Table 3 Drug interactions associated with diminished methadone effects

Pharmacokinetic effects Clinical effects Type of evidence Possible mechanism References

Antibiotics
Fusidic acid Total clearance No side effects were Randomised, prospective trial, Induction of CYP450 46
antipyrine q in group reported by patients; some placebo controlled. Ten enzymes
using fusidic acid 6 patients in 28 day group patients received fusidic acid
28 days developed signs of 500 mg/day 6 14 days; 10
underdosage patients with same dose 6
28 days; 10 patients
received no additional
meds. Antipyrine clearance
used to assess effect on
CYP450 system
Rifampin Q methadone plasma Methadone withdrawal Case Induction of CYP3A4 12, 47
level symptoms

Antivirals/non-nucleoside reverse transcriptase

inhibitors
Efavirenz Marked Q maximum Nine patients described Prospective trial of 11 Induction of CYP3A4 48
plasma methadone symptoms of methadone patients using methadone
concentration, Q AUC withdrawal and beginning therapy
with efavirenz
Nevirapine Three of seven records All seven records had Retrospective chart review Induction of CYP3A4 49
had a documented evidence of opiate of 800 records of HIV-
decrease in methadone withdrawal infected patients
trough level or
subtherapeutic level
36% reduction in Six of eight patients Prospective administration Induction of CYP3A4 50
maximal concentration reported withdrawal of nevirapine to eight patients
of methadone, symptoms
significant Q AUC

Antivirals/nucleoside reverse transcriptase

inhibitors
Abacavir Administration of Two patients of the five Prospective administration Abacavir not expected to 51
both abacavir and reported symptoms of abacavir and ampenavir induce CYP3A4 activity;
ampenavir associated consistent with withdrawal to five patients using the protease inhibitor,
with median 65% methadone ampenavir, is a known
decrease in methadone inducer of CYP3A4 and
concentration more likely the cause of Q
methadone concentration

Antivirals/protease
inhibitors
Amprenavir (see
abacavir statement)
Nelfinavir Complaint of opiate Single case report nelfinavir Induction of CYP3A4, 52
withdrawal within six weeks 750 mg three times a day possible induction of
added to drug regimen P-glycoprotein
Ritonavir/ 40% Q AUC in S- No evidence of withdrawal Prospective pharmacokinetic Ritonavir: induction of 53, 54
saquinavir methadone and 32% reported study of 12 patients using CYP3A4; possible induction
Q AUC in R-methadone methadone who began of P-glycoprotein, induction
400 mg ritonavir and of CYP2C19 and/or CYP2B6
400 mg saquinavir twice to explain greater induction
daily of S-methadone v R-
methadone. In vitro
comparison of inhibition
protency against metabolism
of methadone is ritonavir .
indinavir . saquinavir

Adapted with permission from Eap CB, Buclin T, Baumann P. Interindividual variability of clinical pharmacokinetics of methadone. Clin Pharmacokinet
2002;41:1153–93.15
AUC, area under the curve.

www.postgradmedj.com
 Downloaded from pmj.bmj.com on 20 February 2008
658 Brown, Kraus, Fleming, et al

dose titration, a thorough history for medical risk factors, and 80% in vitro, many of these agents do not exhibit the same
cognisance of medication interactions should avert this degree of inhibition in vivo.15 A summary of medications
potentially catastrophic effect. associated with increased concentrations of methadone are
Due to central opioid receptor activation, somnolence is found in table 2.44–50
quite common during the first weeks of treatment before Drugs which induce enzyme systems responsible for
tolerance to this drug effect is gained. Methadone may also methadone metabolism may result in lowering of methadone
interfere with rapid eye movement sleep and sleep stages 3 levels. It is thought that chronic abuse of alcohol may
and 4. When these changes persist during chronic treatment, increase liver enzymes and reduce methadone levels.19 51
insomnia may occur.18 Patients experiencing this side effect Seizure medications like phenytoin, phenobarbital, and
have lower sleep efficiency, less rapid eye movement, and less carbamazepine are classic examples of CYP3A4 enzyme
slow wave sleep accompanied by sleep disordered breathing. inducers that may lower methadone concentrations.15 Of
Additionally they spend more time in sleep stage 2.19 the antibiotics, rifampin has been shown to interfere with
Methadone maintenance patients may also experience methadone. Of the antiviral medications used for the
subjective cognitive slowing. Objective, controlled data on treatment of HIV, the non-nucleoside reverse transcriptase
this phenomenon are scarce. Tolerance would be expected to inhibitors increase the metabolism of methadone. Drug
this side effect as has been demonstrated with the chronic interactions resulting in lowered methadone concentrations
use of other opioid medications. A European study examining can be found in table 3.17 52–60
the cognitive effects of chronic methadone therapy concluded Methadone levels may be affected by competition for
that methadone treatment was not, in itself, predictive of enzyme metabolism. For example, some feel that binge
impairment in cognitive psychomotor skills; inferior perfor- drinking of alcohol may prevent appropriate metabolism of
mance on tests was more strongly related to sociodemo- methadone, temporarily increasing concentrations.19 One
graphic factors.33 A second study demonstrated that example of preferential metabolism of methadone is its
psychophysical performances and driving aptitude are not interaction with zidovudine, where increased zidovudine
significantly related to methadone dose.34 levels have been described.15 On the other hand, methadone
Weight gain is a commonly reported side effect among appears to decrease the concentration of stavudine and
patients on methadone maintenance. The precise aetiology is didanosine by apparently decreasing their absorption.61
unclear but may involve appetite increase and/or non- Finally, both alcohol and benzodiazepines have been asso-
cardiogenic peripheral oedema. Previous studies have indi- ciated with increased risk for respiratory depression in
cated an onset of weight gain three to six months after patients using opioids.18
initiation of methadone maintenance treatment or after a
sharp dosage increase.32 35
CONCLUSION
Sexual dysfunction is also a common complaint of In summary, methadone has important therapeutic applica-
individuals on chronic methadone. In men, orgasm dysfunc-
tions beyond methadone maintenance for opioid depen-
tion and a decrease in libido are the most common concerns. dence. It is a viable choice for patients with neuropathic pain,
Spermatic dysmotility has also been described.36 37 Whether
for pain resistant to treatment with other opioid analgesics,
or not fertility is adversely affected has yet to be firmly and for situations where dose limiting side effects occur from
established. Several studies that indicate subnormal levels of other opioid agents. Practitioners who prescribe methadone
plasma testosterone in men maintained on methadone may need to be familiar with its unique pharmacokinetic profile,
account for these side effects, though a dose effect relation- side effects, and potential drug interactions to ensure safe,
ship has yet to be discovered.38–42 Women may experience effective use of this agent.
dysfunction of libido as well as oligomenorrhoea or amenor-
rhoea.32 The aetiology of and potential treatments for these .....................
effects are unclear. Authors’ affiliations
Up to 65% of patients report constipation as a direct effect R Brown, University of Wisconsin Department of Family Medicine and
of methadone.32 Tolerance to this peripheral opioid effect may Department of Population Health Sciences, and Madison Health Services
not develop, often necessitating a scheduled bowel regimen Methadone Treatment Facility, Madison, Wisconsin, USA
during treatment with methadone.43 C Kraus, University of Wisconsin Department of Pharmacy, Madison,
Wisconsin, USA
M Fleming, University of Wisconsin Department of Family Medicine,
DRUG INTERACTIONS WITH METHADONE Madison, Wisconsin, USA
There are many potential drug interactions with methadone. S Reddy, University of Wisconsin Medical School, Madison, Wisconsin,
However, it is difficult to study drug interactions because USA
methadone has a long half life, and time to steady state
concentration after a change due to a drug interaction may REFERENCES
require up to 10 days. Many of the drug interactions cited in 1 Morley J, Makin M. The use of methadone in cancer pain poorly responsive to
the literature have not been rigorously investigated.19 In other opiates. Pain Reviews 1998;5:51–8.
addition, even though statistically significant change in 2 Bruera E, Pereira J, Watanabe S, et al. Opioid rotation in patients with cancer
pain. A retrospective comparison of dose ratios between methadone,
methadone concentration may occur as a result of a drug- hydromorphone, and morphine. Cancer 1996;78:852–7.
drug interaction, the clinical outcome may not be significant, 3 Ayonrinde OT, Bridge DT. The rediscovery of methadone for cancer pain
since methadone has such a wide therapeutic window, and management [comment]. Med J Aust 2000;173:536–40.
because methadone’s half life varies significantly between 4 Bruera E, MacMillan K, Hanson J, et al. Palliative care in a cancer center.
Results in 1984 versus 1987. J Pain Symptom Manage 1990;5:1–5.
individuals.44 In the setting of a potential drug interaction, 5 Crews J, Sweeney N, Denson D. Clinical efficiency of methadone in patients
therefore, it is reasonable to institute a dosing regimen as refractory to other mu-opioid receptor agonist analgesics for management of
described in tables 2 or 3, and monitor the patient closely for terminal cancer pain. Cancer 1993;72:2266–72.
6 de Conno F, Groff L, Brunelli C, et al. Clinical experience with oral methadone
signs of supratherapeutic dosing (sedation, euphoria). administration in the treatment of 196 advanced cancer patients. J Clin Oncol
Drug interactions with methadone most commonly occur 1996;14:2836–42.
due to inhibition or induction of liver enzymes. Although 7 Leng G, Finnegan M. Successful use of methadone in nociceptive cancer pain
drugs like older macrolide antibiotics (troleandomycin), unresponsive to morphine. Palliat Med 1994;8:153–5.
8 Mercadante S, Casuccio A, Fulfaro F, et al. Switching from morphine to
ketoconazole, and diazepam are able to inhibit CYP3A4 methadone to improve analgesia and tolerability in cancer patients: a
metabolism of methadone to its inactive metabolite by up to prospective study. J Clin Oncol 2001;19:2898–904.

www.postgradmedj.com
 Downloaded from pmj.bmj.com on 20 February 2008
Methadone and chronic pain 659

9 Ripamonti C, Bianchi M. The use of methadone for cancer pain. Hematol 36 Ragni G, De Lauretis L, Gambaro V, et al. Semen evaluation in heroin and
Oncol Clin North Am 2002;16:543–55. methadone addicts. Acta Eur Fertil 1985;16:245–9.
10 Daeninck PJ, Bruera E. Reduction in constipation and laxative requirements 37 Cicero TJ, Bell RD, Wiest WG, et al. Function of the male sex organs in heroin
following opioid rotation to methadone: a report of four cases. J Pain and methadone users. N Engl J Med 1975;292:882–7.
Symptom Manage 1999;18:303–9. 38 Mendelson JH, Mello NK. Plasma testosterone levels during chronic heroin use
11 Gardner-Nix JS. Oral methadone for managing chronic nonmalignant pain. and protracted abstinence: study of Hong Kong addicts. NIDA Res Monogr
J Pain Symptom Manage 1996;11:321–8. 1978;19:142–8.
12 Belluck P. Methadone, once the way out, suddenly grows as a killer drug. 39 Mendelson JH, Mendelson JE, Patch VD. Plasma testosterone levels in heroin
New York Times 9 February 2003 (section 1). addiction and during methadone maintenance. J Pharmacol Exp Ther
13 Press A. Methadone overdose deaths on rise in MD. The State 7 January 2004 1975;192:211–17.
(section 1). 40 Mendelson JH, Meyer RE, Ellingboe J, et al. Effects of heroin and methadone
14 Hammack L. Methadone deaths on rise in Southwest Virginia. The Roanoke on plasma cortisol and testosterone. J Pharmacol Exp Ther
Times 20 July 2002. 1975;195:296–302.
15 Eap C, Buclin T, Baumann P. Interindividual variability of the clinical 41 Ragni G, De Lauretis L, Bestetti O, et al. Gonadal function in male heroin and
pharmacokinetics of methadone. Clin Pharmacokinet 2002;41:1153–93. methadone addicts. Int J Androl 1988;11:93–100.
16 Inturrisi CE. Clinical pharmacology of opiods for pain. Clin J Pain 42 Spring WD Jr, Willenbring ML, Maddux TL. Sexual dysfunction and
2002;18:S3–13. psychological distress in methadone maintenance. Int J Addict
17 Lotsch J, Skarke C, Tegeder I, et al. Drug interactions with patient-controlled 1992;27:1325–34.
analgesia. Clin Pharmacokinet 2001;41:31–57. 43 Yuan C, Foss J, O’Connor M, et al. Gut motility and transit changes in patients
18 White J, Irvine R. Mechanisms of fatal opioid overdose. Addiction receiving long-term methadone maintenance. J Clin Pharmacol
1999;94:961–72. 1998;38:931–5.
19 Moolchan E, Umbricht A, Epstein D. Therapeutic drug monitoring in 44 Cobb M, Desai J, Brown L Jr, et al. The effect of fluconazole on the clinical
methadone maintenance: choosing a matrix. J Addict Dis 2001;20:55–73. pharmacokinetics of methadone. Clin Pharmacol Ther 1998;63:655–62.
20 Ball J, Ross A. The effectiveness of methadone maintenance treatment. New 45 Herrlin K, Segerdahl M, Gustafsson LL, et al. Methadone, ciprofloxacin, and
York, NY: Springer-Verlag, 1991. adverse drug reactions. Lancet 2000;356:2069–70.
46 Bertschy G, Eap B, Powell K, et al. Fluoxetine addition to methadone addicts:
21 National Institute on Drug Abuse. Heroin abuse and addiction. Rockville, MD:
pharmacokinetic aspects. Ther Drug Monit 1996;18:570–2.
US Department of Health and Human Services, National Institute on Drug
47 Alderman CP, Frith PA. Fluvoxamine-methadone interaction. Aust N Z J
Abuse, 2000 (publication number 00–4165).
Psychiatry 1999;33:99–101.
22 Gunne L, Gronbladh L. The Swedish methadone maintenance program: a
48 DeMaria PA Jr, Serota RD. A therapeutic use of the methadone fluvoxamine
controlled study. Drug Alcohol Depend 1981;7:249–56.
drug interaction. J Addict Dis 1999;18:5–12.
23 Newman R, Whitehill W. Double-blind comparison of methadone and
49 Begre S, von Bardeleben U, Ladewig D, et al. Paroxetine increases steady-
placebo maintenance treatments of narcotic addicts in Hong Kong. Lancet
state concentrations of (R)-methadone in CYP2D6 extensive but not poor
1979;ii:485–8.
metabolizers. J Clin Psychopharmacol 2002;22:211–5.
24 Stenbacka M, Leifman A, Romelsjo A. The impact of methadone on 50 Hamilton SP, Nunes EV, Janal M, et al. The effect of sertraline on methadone
consumption of inpatient care and mortality with special reference to HIV plasma levels in methadone-maintenance patients. Am J Addict 2000;9:63–9.
status. Subst Use Misuse 1998;33:2819–34. 51 Ottomanelli G. Methadone patients and alcohol abuse. J Subst Abuse Treat
25 Ward J, Hall W, Mattick R. Role of maintenance treatment in opioid 1999;16:113–21.
dependence. Lancet 1999;353:221–6. 52 Reimann G, Barthel B, Rockstroh JK, et al. Effect of fusidic acid on the hepatic
26 Barnett P, Hui S. The cost-effectiveness of methadone maintenance. Mt cytochrome P450 enzyme system. Int J Clin Pharmacol Ther 1999;37:562–6.
Sinai J Med 2000;67:365–74. 53 Raistrick D, Hay A, Wolff K. Methadone maintenance and tuberculosis
27 Ling W, Charuvastra C, Kaim SC, et al. Methadyl acetate and methadone as treatment. BMJ 1996;313:925–6.
maintenance treatments for heroin addicts. A Veterans’ Administration 54 Clarke SM, Mulcahy FM, Tjia J, et al. The pharmacokinetics of methadone in
cooperative study. Arch Gen Psychiatry 1976;33:709–20. HIV-positive patients receiving the non-nucleoside reverse transcriptase
28 Strain E, Stitzer M, Liebson I, et al. Dose-response effects of methadone in the inhibitor efavirenz. Br J Clin Pharmacol 2001;51:213–7.
treatment of opioid dependence. Ann Intern Med 1993;119:23–7. 55 Altice FL, Friedland GH, Cooney EL. Nevirapine induced opiate withdrawal
29 Ripamonti C, Groff L, Brunelli C, et al. Switching from morphine to oral among injection drug users with HIV infection receiving methadone. AIDS
methadone in treating cancer pain: what is the equianalgesic dose ratio? J Clin 1999;13:957–62.
Oncol 1998;16:3216–21. 56 Clarke SM, Mulcahy FM, Tjia J, et al. Pharmacokinetic interactions of
30 Nauck F, Ostgathe C, Klaschik E, et al. A German model of methadone nevirapine and methadone and guidelines for use of nevirapine to treat
conversion [abstract 90]. Abstracts of the 13th MASCC/ISOO International injection drug users. Clin Infect Dis 2001;33:1595–7.
Symposium. Copenhagen, 2001. 57 Bart PA, Rizzardi PG, Gallant S, et al. Methadone blood concentrations are
31 Reilly PM, Sees KL, Shopshire MS, et al. Self-efficacy and illicit opioid use in a decreased by the administration of abacavir plus amprenavir. Ther Drug
180-day methadone detoxification treatment. J Consult Clin Psychol Monit 2001;23:553–5.
1995;63:158–62. 58 McCance-Katz EF, Farber S, Selwyn PA, et al. Decrease in methodone levels
32 Dyer KR, White JM. Patterns of symptom complaints in methadone with nelfinavir mesylate. Am J Psychiatry 2000;157:481.
maintenance patients. Addiction 1997;92:1445–55. 59 Gerber JG, Rosenkranz S, Segal Y, et al. Effect of ritonavir/saquinavir on
33 Specka M, Finkbeiner T, Lodemann E, et al. Cognitive-motor performance of stereoselective pharmacokinetics of methadone: results of AIDS Clinical Trials
methadone-maintained patients. Eur Addict Res 2000;6:8–19. Group (ACTG) 401. J Acquir Immune Defic Syndr 2001;27:153–60.
34 Hauri-Bionda R, Bar W, Friedrich-Koch A. [Driving fitness/driving capacity of 60 Iribarne C, Berthou F, Carlhant D, et al. Inhibition of methadone and
patients treated with methadone]. Schweiz Med Wochenschr buprenorphine N-dealkylations by three HIV-1 protease inhibitors. Drug
1998;128:1538–47. Metab Dispos 1998;26:257–60.
35 Longwell B, Betz T, Horton H, et al. Weight gain and edema on methadone 61 Rainey PM. HIV drug interactions: the good, the bad, and the other. Ther Drug
maintenance therapy. Int J Addict 1979;14:329–35. Monit 2002;24:26–31.

www.postgradmedj.com