Abstract
OBJECTIVE:
This research was designed as a pilot proof-of-concept study to evaluate the use of low-dose methadone in post-herpetic neuralgia patients who remained refractory after first and second line post-herpetic neuralgia treatments and had indications for adding an opioid agent to their current drug regimens.
METHODS:
This cross-over study was double blind and placebo controlled. Ten opioid naïve post-herpetic neuralgia patients received either methadone (5 mg bid) or placebo for three weeks, followed by a 15-day washout period and a second three-week treatment with either methadone or placebo, accordingly. Clinical evaluations were performed four times (before and after each three-week treatment period). The evaluations included the visual analogue scale, verbal category scale, daily activities scale, McGill pain questionnaire, adverse events profile, and evoked pain assessment. All patients provided written informed consent before being included in the study. ClinicalTrials.gov: NCT01752699
RESULTS:
Methadone, when compared to placebo, did not significantly affect the intensity of spontaneous pain, as measured by the visual analogue scale. The intensity of spontaneous pain was significantly decreased after the methadone treatment compared to placebo on the category verbal scale (50% improved after the methadone treatment, none after the placebo, p = 0.031). Evoked pain was reduced under methadone compared to placebo (50% improved after the methadone treatment, none after the placebo, p = 0.031). Allodynia reduction correlated with sleep improvement (r = 0.67, p = 0.030) during the methadone treatment. The side effects profile was similar between both treatments.
Conclusions:
Methadone seems to be safe and efficacious in post-herpetic neuralgia. It should be tried as an adjunctive treatment for post-herpetic neuralgia in larger prospective studies.
Post-Herpetic Neuralgia; Methadone; Neuropathic Pain
INTRODUCTION
Methadone was first described over fifty years ago. It is a synthetic opioid agonist
that exhibits a potent antagonist effect on glutamate N-methyl-D-aspartate (NMDA)
receptors. Methadone is highly bound to proteins (alfa-1-acid-glycoprotein), highly
lipophilic and metabolized by the liver (mainly by the cytochrome P450 CYP 3A3/4
isoenzyme); it has no known active metabolites. Methadone has a high intestinal
absorption, and its bioavailability is approximately 80%, with much less
inter-individual variability compared to other opioids, such as oral morphine. One
unique feature of methadone is that is has a robust distribution phase with a short
lasting (alpha) half-life of approximately 3 hours, followed by an extended
elimination phase (beta) ranging from 12 to 60 hours; it also displays large
inter-individual variability. This elimination phase may result in toxicity and drug
accumulation. Most of the drug is excreted in feces with no significant accumulation
in patients with renal impairment. Despite its long term use in drug addiction and
in cancer pain patients, there is a great paucity of studies on methadone in
neuropathic pain syndromes. Neuropathic pain is present in 7% of the general
population (11. Bouhassira D, Lanteri-Minet M, Attal N, Laurent B, Touboul C.
Prevalence of chronic pain with neuropathic characteristics in the general
population. Pain. 2008;136(3):380-7,
http://dx.doi.org/10.1016/j.pain.2007.08.013.
http://dx.doi.org/10.1016/j.pain.2007.08...
) and may represent up to 60% of
patients with cancer-related pain. Opioids are effective for neuropathic pain and
are used as second and third line treatments in this population. However, most of
the available evidence concerns the use of tramadol and extended release oxycodone.
Other opioids, such as hydromorphone and methadone, were seldom evaluated for this
pain syndrome. Methadone is an inexpensive and widely available drug in many
countries, but it is also a potent NMDA inhibitor, which could potentially increase
its analgesic effects in neuropathic pain patients. The aim of this pilot
proof-of-principle study was to evaluate the use of low-dose methadone in refractory
post-herpetic neuralgia (PHN) patients who remained refractory after undergoing
first and second line treatments and had indications for adding an opioid to their
current drug regimen. The main outcome measurement was pain intensity reduction, and
the secondary outcomes were patient safety, changes in pain interference in daily
life and the different effects of chronic pain.
METHODS
Patients
The aim of this pilot proof-of-concept study was to assess the safety and
efficacy of methadone in PHN patients. Patients with chronic (>6 months)
symptomatic PHN with visual analogical scale (VAS) scores >40/100 mm
despite using first and second line treatment drugs (e.g., tricyclic
antidepressants, venlafaxine and gabapentinoids) were recruited from the Pain
Center of the Hospital das Clínicas, University of São Paulo, Brazil.
All patients were opioid naïve. The PHN diagnosis was based on current
diagnostic criteria (22. Treede RD, Jensen TS, Campbell JN, Cruccu G, Dostrovsky JO,
Griffin JW, et al. Neuropathic pain: redefinition and a grading system for
clinical and research purposes. Neurology. 2008;70(18):1630-5,
http://dx.doi.org/10.1212/01.wnl.0000282763.29778.59.
http://dx.doi.org/10.1212/01.wnl.0000282...
) for defined
neuropathic pain. Pain was located in the cervical, dorsal or trigeminal
areas.
The study was approved by our local institutional review board and registered at ClinicalTrials.gov (0078/11 and NCT01752699, respectively). All patients provided written informed consent before being included in the study.
Study design
In this crossover, double-blind, randomized trial, all participants received either methadone 5 mg or placebo (bid) for three weeks, followed by a 3-week washout period and then another three-week treatment period with methadone and placebo, according to the randomized treatment sequence. The methadone and placebo pills looked identical.
Clinical assessment
All participants were evaluated before and after each treatment period, for a total of four assessments (two at baseline and two at the end of each three-week treatment period). All clinical assessments were similar and included the following details:
-
-
spontaneous pain (SP) intensity using a VAS;
-
evoked pain (EP), dynamic mechanical allodynia intensity in the painful area was used to study EP, and a gentle stroke with a standardized brush (Senselab Brush 05, Somedic AB, Hörby, Skane, Sweden) at a speed of 2 cm/s and covering a 6-cm distance inside the PHN painful area was used; EP was scored as none ( = 0), mild ( = 1), moderate ( = 2), or severe ( = 3) after three strokes;
-
the Category Verbal Scale (CVS) was measured as mild, moderate, and severe pain intensity (33. Breivik EK, Bjornsson GA, Skovlund E. A comparison of pain rating scales by sampling from clinical trial data. Clin J Pain. 2000;16(1):22-8.);
-
the daily activities scale (AS) (items from the Brief Pain Questionnaire) was used to measure the impact of pain on different activities of daily living and was scored as normal ( = 0), decreased ( = 1), or abolished ( = 2) (44. Daut RL, Cleeland CS, Flanery RC. Development of the Wisconsin Brief Pain Questionnaire to assess pain in cancer and other diseases. Pain. 1983;17(2):197-210, http://dx.doi.org/10.1016/0304-3959(83)90143-4.
http://dx.doi.org/10.1016/0304-3959(83)9... ); -
the McGill Pain Questionnaire (MPQ) (55. Pimenta C, Teixeira M. Questionário de Dor McGill: proposta de adaptação para a língua portuguesa. Rev Esc Enf USP. 1996;30(3):473-83.); and
-
adverse events were assessed by direct questioning patients on the presence of new symptoms presenting during treatment.
-
Data analysis
Each participant's baseline characteristics were expressed as descriptive
statistics with average ± standard deviation. A non-parametric test for
repeated series (the Wilcoxon signed-rank test) was used because the data did
not show normal distribution according to the Kolmogorov-Smirnov test. The
proportion of responders vs. non-responders and the total
number of participants with improved or aggravated symptoms (scores) under
methadone compared to placebo were compared using Fisher's exact test.
Correlation analyses were performed using Spearman's correlation
coefficient. Sample size was calculated based on the data available on the
effects of methadone in other neuropathic pain syndromes (66. Dell RB, Holleran S, Ramakrishnan R. Sample size determination.
Ilar J. 2002;43(4):207-13,
http://dx.doi.org/10.1093/ilar.43.4.207.
http://dx.doi.org/10.1093/ilar.43.4.207...
,77. Morley JS, Bridson J, Nash TP, Miles JB, White S, Makin MK.
Low-dose methadone has an analgesic effect in neuropathic pain: a double-blind
randomized controlled crossover trial. Palliat Med. 2003;17(7):576-87,
http://dx.doi.org/10.1191/0269216303pm815oa.
http://dx.doi.org/10.1191/0269216303pm81...
). Sample size
estimation was calculated based on the information available from open-label
studies that suggested a responder rate close to 50% under methadone (66. Dell RB, Holleran S, Ramakrishnan R. Sample size determination.
Ilar J. 2002;43(4):207-13,
http://dx.doi.org/10.1093/ilar.43.4.207.
http://dx.doi.org/10.1093/ilar.43.4.207...
,88. Moulin DE, Palma D, Watling C, Schulz V. Methadone in the
management of intractable neuropathic noncancer pain. Can J Neurol
Sci. 2005;32(3):340-3.
9. Watson CP. Methadone for neuropathic pain: a new use for an old
drug? Can J Neurol Sci. 2005;32(3):271-2.-1010. Terpening CM, Johnson WM. Methadone as an analgesic: a review of
the risks and benefits. W V Med J.
2007;103(1):14-8.) In all instances, the
level of significance was set at p<0.05.
RESULTS
Patient characteristics
Ten patients (6 females, mean age 71±21 years) with neuropathic pain secondary to PHN (mean duration of pain 41±19 months) were included in the study and completed the two treatment phases. They experienced pain in the following dermatomes/areas: cervical n = 3, dorsal n = 4, and trigeminal n = 3.
The treatment had the following effects on the patients' pain and general activity levels.
Methadone did not significantly affect the intensity of spontaneous pain, as measured by the VAS compared to placebo.
The intensity of spontaneous pain was significantly decreased after the methadone treatment compared to placebo on the CVS (50% improved after methadone, none after placebo, p = 0.031). EP was reduced with methadone compared to placebo (50% improved after methadone, none after placebo, p = 0.031) (Table 1).
The activities of daily living and McGill Pain Questionnaire scores did not significantly change after the active treatment. In particular, methadone did not have any negative impact on daily activities, such as concentration, mood or sleep.
Correlation analyses
Allodynia reduction correlated with sleep improvement (r = 0.67, p = 0.030) during the methadone treatment. Older age was associated with greater impacts on concentration (r = -0.69, p = 0.024) and daily activities (r = 0.69, p = 0.025).
Side effects
The frequency of reported adverse events, such as constipation, nausea and dizziness, did not differ significantly in either treatment period. None of the participants left the study.
DISCUSSION
We have demonstrated that at low doses, methadone decreased the pain intensity scores and evoked pain levels in PHN patients and had a satisfactory safety profile. This controlled study is one of the few to study methadone's effect on neuropathic pain and the only one to evaluate a specific patient group, such as PHN patients.
There is a great paucity of randomized controlled studies of methadone in chronic
pain. Note, there are no placebo-controlled studies on the use of this drug in
cancer patients, which is understandable because of ethical issues. Case series have
suggested that methadone could be used long term in neuropathic pain patients (1111. Altier N, Dion D, Boulanger A, Choinière M. Managment of
Chronic Neuropathic pain with methadone: A review of 13 cases.
Clin J Pain. 2005;21:364-9.,1212. Altier N, Dion D, Boulanger A, Choinière M. Sucessful use
of methadone in the treatment of chronic neuropathic pain arising from burn
injuries: a case-study. Burns. 2001;27:771-5,
http://dx.doi.org/10.1016/S0305-4179(01)00032-8.
http://dx.doi.org/10.1016/S0305-4179(01)...
).
Until now, only one placebo controlled study evaluated its efficacy in a small
sample of heterogeneous neuropathic pain syndromes (1313. Cherny N. Is oral methadone better than placebo or other
oral/transdermal opioids in the management of pain? Palliat Med.
2011;25(5):488-93, http://dx.doi.org/10.1177/0269216310397687.
http://dx.doi.org/10.1177/02692163103976...
). In this study, methadone was used in a rather peculiar regimen,
taken on alternate days at 10 and 20 mg/day doses. It was found that methadone at 20
mg/day had a significant effect over placebo in each 20-day trial duration (77. Morley JS, Bridson J, Nash TP, Miles JB, White S, Makin MK.
Low-dose methadone has an analgesic effect in neuropathic pain: a double-blind
randomized controlled crossover trial. Palliat Med. 2003;17(7):576-87,
http://dx.doi.org/10.1191/0269216303pm815oa.
http://dx.doi.org/10.1191/0269216303pm81...
). An open-label study evaluated the analgesic
effect of methadone against morphine in cancer pain patients. The analgesic effects
were similar, but methadone was associated with less frequent dry mouth and more
frequent headaches, and while the morphine dose had to be significantly titrated
during the 14-day trial, the methadone dose remained the same (1414. Ventafridda V, Ripamonti C, Bianchi M, Sbanotto A, De Conno F. A
randomized study on oral administration of morphine and methadone in the
treatment of cancer pain. J Pain Symptom Manage. 1986;1(4):203-7,
http://dx.doi.org/10.1016/S0885-3924(86)80042-2.
http://dx.doi.org/10.1016/S0885-3924(86)...
). Similar results were reported (1515. Gourlay GK, Cherry DA, Cousins MJ. A comparative study of the
efficacy and pharmacokinetics of oral methadone and morphine in the treatment of
severe pain in patients with cancer. Pain. 1986;25(3):297-312,
http://dx.doi.org/10.1016/0304-3959(86)90234-4.
http://dx.doi.org/10.1016/0304-3959(86)9...
) in a parallel trial comparing methadone and morphine in
cancer pain patients. In a more recent study (1616. Bruera E, Palmer JL, Bosnjak S, Rico MA, Moyano J, Sweeney C, et
al. Methadone versus morphine as a first-line strong opioid for cancer pain: a
randomized, double-blind study. J Clin Oncol.
2004;22(1):185-92.), the authors suggested that methadone would be as effective as
morphine in cancer pain patients with or without neuropathic pain. However, the
external validity of this study remained limited because of the extremely high
drop-out rate observed, which was most likely caused by the high dose conversion
ratio from morphine to methadone (2:1) and the fixed dose regimen chosen, which
would force patients in the methadone group to receive relatively more drug than the
morphine arm, with no possibility to decrease it without leaving the study.
The latest study (1717. Mercadante S, Porzio G, Ferrera P, Fulfaro F, Aielli F, Verna L, et al. Sustained-release oral morphine versus transdermal fentanyl and oral methadone in cancer pain management. Eur J Pain. 2008;12(8):1040-6.) included cancer pain patients in an open-label parallel design trial to receive either methadone, sustained release morphine or transdermal fentanyl. The authors found no difference in pain relief or in the negative impacts of quality of life or adverse events. However, methadone was associated with a substantially lower treatment cost than the other treatments.
Excitatory amino acids have been implicated in the occurrence of neuropathic pain,
specifically through NMDA receptors, which have been implicated in the occurrence of
opioid tolerance and are considered to play a major role in the central
sensitization seen in neuropathic pain patients. Because methadone is a potent
opioid agonist and an NMDA antagonist, it has been suggested that it would have
efficacy in neuropathic pain. Methadone has been shown to attenuate mechanical and
cold allodynia in experimental models of both peripheral and central neuropathic
pain (1818. Erichsen HK, Hao JX, Xu XJ, Blackburn-Munro G. Comparative
actions of the opioid analgesics morphine, methadone and codeine in rat models
of peripheral and central neuropathic pain. Pain, 2005;116(3):347-58,
http://dx.doi.org/10.1016/j.pain.2005.05.004.
http://dx.doi.org/10.1016/j.pain.2005.05...
), exhibiting anti-allodynic affects
superior to oxycodone and morphine (1919. Lemberg K, Kontinen VK, Viljakka K, Kylanlahti I, Yli-Kauhaluoma
J, Kalso E. Morphine, oxycodone, methadone and its enantiomers in different
models of nociception in the rat. Anesth Analg, 2006;102(6):1768-74,
http://dx.doi.org/10.1213/01.ane.0000205751.88422.41.
http://dx.doi.org/10.1213/01.ane.0000205...
). It
has also been shown that the blockade of NMDA receptors plays an important role in
the analgesic effects observed in experimental models of peripheral neuropathic pain
(2020. Sotgiu ML, Valente M, Storchi R, Caramenti G, Biella GE.
Cooperative N-methyl-D-aspartate (NMDA) receptor antagonism and mu-opioid
receptor agonism mediate the methadone inhibition of the spinal neuron
pain-related hyperactivity in a rat model of neuropathic pain. Pharmacol Res.
2009;60(4):284-90,
http://dx.doi.org/10.1016/j.phrs.2009.04.002.
http://dx.doi.org/10.1016/j.phrs.2009.04...
), which may also be related to its
norepinephrine and serotonin reuptake blocker properties (2121. Toombs JD, Kral LA. Methadone treatment for pain states. Am Fam
Physician. 2005;71(7):1353-8.). The preferential effect of methadone in dynamic mechanical
allodynia found in the present study and its correlation with sleep improvement is
an original finding and confirms the findings from experimental studies. Larger
controlled trials of the use of methadone in neuropathic pain must be performed
because it is an inexpensive opioid that has pharmacological particularities, such
as long half-life and NMDA antagonism that make it an attractive option to opioids
currently available for this pain syndrome. Placebo use in pain patients frequently
raises ethical concerns. Despite the possible analgesic effect of methadone to treat
PHN a priori, it is not currently approved as a treatment option for neuropathic
pain, and it is not widely available in Europe or in many Latin American countries
for this indication mainly because of the lack of clinical evidence attesting to its
efficacy, such as this brief pilot study. Methadone and placebo were added to the
current analgesic regimen of patients who were already receiving the best
pharmacological treatment available at our institution at the time of the study.
Thus, a more effective neuropathic pain treatment was not withheld because of
participating in this study protocol; both methadone and placebo were used as an
“add-on” treatment. As part of our current ethical recommendations,
all patients who improved while taking methadone were offered the medication on a
long-term treatment basis after the study ended.
REFERENCES
-
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» http://dx.doi.org/10.1016/j.pain.2007.08.013 -
2Treede RD, Jensen TS, Campbell JN, Cruccu G, Dostrovsky JO, Griffin JW, et al. Neuropathic pain: redefinition and a grading system for clinical and research purposes. Neurology. 2008;70(18):1630-5, http://dx.doi.org/10.1212/01.wnl.0000282763.29778.59.
» http://dx.doi.org/10.1212/01.wnl.0000282763.29778.59 -
3Breivik EK, Bjornsson GA, Skovlund E. A comparison of pain rating scales by sampling from clinical trial data. Clin J Pain. 2000;16(1):22-8.
-
4Daut RL, Cleeland CS, Flanery RC. Development of the Wisconsin Brief Pain Questionnaire to assess pain in cancer and other diseases. Pain. 1983;17(2):197-210, http://dx.doi.org/10.1016/0304-3959(83)90143-4.
» http://dx.doi.org/10.1016/0304-3959(83)90143-4 -
5Pimenta C, Teixeira M. Questionário de Dor McGill: proposta de adaptação para a língua portuguesa. Rev Esc Enf USP. 1996;30(3):473-83.
-
6Dell RB, Holleran S, Ramakrishnan R. Sample size determination. Ilar J. 2002;43(4):207-13, http://dx.doi.org/10.1093/ilar.43.4.207.
» http://dx.doi.org/10.1093/ilar.43.4.207 -
7Morley JS, Bridson J, Nash TP, Miles JB, White S, Makin MK. Low-dose methadone has an analgesic effect in neuropathic pain: a double-blind randomized controlled crossover trial. Palliat Med. 2003;17(7):576-87, http://dx.doi.org/10.1191/0269216303pm815oa.
» http://dx.doi.org/10.1191/0269216303pm815oa -
8Moulin DE, Palma D, Watling C, Schulz V. Methadone in the management of intractable neuropathic noncancer pain. Can J Neurol Sci. 2005;32(3):340-3.
-
9Watson CP. Methadone for neuropathic pain: a new use for an old drug? Can J Neurol Sci. 2005;32(3):271-2.
-
10Terpening CM, Johnson WM. Methadone as an analgesic: a review of the risks and benefits. W V Med J. 2007;103(1):14-8.
-
11Altier N, Dion D, Boulanger A, Choinière M. Managment of Chronic Neuropathic pain with methadone: A review of 13 cases. Clin J Pain. 2005;21:364-9.
-
12Altier N, Dion D, Boulanger A, Choinière M. Sucessful use of methadone in the treatment of chronic neuropathic pain arising from burn injuries: a case-study. Burns. 2001;27:771-5, http://dx.doi.org/10.1016/S0305-4179(01)00032-8.
» http://dx.doi.org/10.1016/S0305-4179(01)00032-8 -
13Cherny N. Is oral methadone better than placebo or other oral/transdermal opioids in the management of pain? Palliat Med. 2011;25(5):488-93, http://dx.doi.org/10.1177/0269216310397687.
» http://dx.doi.org/10.1177/0269216310397687 -
14Ventafridda V, Ripamonti C, Bianchi M, Sbanotto A, De Conno F. A randomized study on oral administration of morphine and methadone in the treatment of cancer pain. J Pain Symptom Manage. 1986;1(4):203-7, http://dx.doi.org/10.1016/S0885-3924(86)80042-2.
» http://dx.doi.org/10.1016/S0885-3924(86)80042-2 -
15Gourlay GK, Cherry DA, Cousins MJ. A comparative study of the efficacy and pharmacokinetics of oral methadone and morphine in the treatment of severe pain in patients with cancer. Pain. 1986;25(3):297-312, http://dx.doi.org/10.1016/0304-3959(86)90234-4.
» http://dx.doi.org/10.1016/0304-3959(86)90234-4 -
16Bruera E, Palmer JL, Bosnjak S, Rico MA, Moyano J, Sweeney C, et al. Methadone versus morphine as a first-line strong opioid for cancer pain: a randomized, double-blind study. J Clin Oncol. 2004;22(1):185-92.
-
17Mercadante S, Porzio G, Ferrera P, Fulfaro F, Aielli F, Verna L, et al. Sustained-release oral morphine versus transdermal fentanyl and oral methadone in cancer pain management. Eur J Pain. 2008;12(8):1040-6.
-
18Erichsen HK, Hao JX, Xu XJ, Blackburn-Munro G. Comparative actions of the opioid analgesics morphine, methadone and codeine in rat models of peripheral and central neuropathic pain. Pain, 2005;116(3):347-58, http://dx.doi.org/10.1016/j.pain.2005.05.004.
» http://dx.doi.org/10.1016/j.pain.2005.05.004 -
19Lemberg K, Kontinen VK, Viljakka K, Kylanlahti I, Yli-Kauhaluoma J, Kalso E. Morphine, oxycodone, methadone and its enantiomers in different models of nociception in the rat. Anesth Analg, 2006;102(6):1768-74, http://dx.doi.org/10.1213/01.ane.0000205751.88422.41.
» http://dx.doi.org/10.1213/01.ane.0000205751.88422.41 -
20Sotgiu ML, Valente M, Storchi R, Caramenti G, Biella GE. Cooperative N-methyl-D-aspartate (NMDA) receptor antagonism and mu-opioid receptor agonism mediate the methadone inhibition of the spinal neuron pain-related hyperactivity in a rat model of neuropathic pain. Pharmacol Res. 2009;60(4):284-90, http://dx.doi.org/10.1016/j.phrs.2009.04.002.
» http://dx.doi.org/10.1016/j.phrs.2009.04.002 -
21Toombs JD, Kral LA. Methadone treatment for pain states. Am Fam Physician. 2005;71(7):1353-8.
Publication Dates
-
Publication in this collection
July 2013
History
-
Received
30 Dec 2012 -
Reviewed
14 Feb 2013 -
Accepted
15 Mar 2013