Improved Pain Control in Terminally Ill Cancer Patients by Introducing Low-Dose Oral Methadone in Addition to Ongoing Opioid Treatment

Abstract

Background:

Cancer pain is often not well controlled and there is a need for improved treatment strategies. Methadone exhibits unique properties among opioids and recent reports show promising results from adding a low dose of methadone to regular opioid therapy.

Objective:

To examine the effects of oral low-dose methadone added to regular scheduled opioids in terminally ill patients with complex cancer-related pain.

Design:

This was a retrospective chart review.

Setting/Subjects:

All patients with advanced cancer treated in a specialized palliative care unit who had received oral methadone in addition to another regular opioid were identified.

Measurements:

Intensity of pain, opioid doses, and occurrence of sedation, delirium, and respiratory depression were obtained from the patients' medical records for a period of one week after initiation of methadone.

Results:

Eighty patients were included. The median daily methadone dose was 10 mg during the treatment period. Eighty percent of the patients had improved pain control (p < 0.001). There was an increased risk for sedation and delirium, most pronounced in patients living 14 days or less after the start of methadone. No patient experienced respiratory depression.

Conclusion:

Addition of low-dose oral methadone to regular high-dose opioid treatment in cancer patients with complex pain close to death improves pain control, but also increases the risk for sedation and delirium.

Introduction

Pain management in palliative care patients with advanced cancer has improved over the last years due to better understanding of pain mechanisms, new guidelines, as well as attempts to tailor a mechanism-based treatment targeting each pain component (i.e., nociceptive, inflammatory, neuropathic pain).^1–3 Still, two thirds of patients with advanced, metastatic, or terminal disease have pain and more than one third of patients grade their pain as moderate or severe.³

In palliative care, opioids are the most frequent drugs used for the treatment of cancer-related pain, but have variable effects on neuropathic pain. Whereas early neuropathic pain components and ongoing neuropathic painful processes might respond well, chronic neuropathic pain sometimes does not respond to opioid therapy at all.^4,5 Moreover, central sensitization can cause an accelerated state of pain despite no progressive tissue damage.⁶ This central sensitization, which may reduce opioid sensitivity, is partly mediated by activation of the N-methyl-d-aspartate (NMDA) receptor.⁷ There is also evidence that NMDA receptors are involved in the development of allodynia, hyperalgesia, opioid tolerance, and opioid-resistant neuropathic pain.⁸

Methadone is an opioid that differs from other opioids. It binds to the mu-opioid receptor, but also stimulates kappa and delta receptors, inhibits NMDA-receptors, and acts on the pain modulating descending tracts in the medulla, affecting reuptake of serotonin and norepinephrine.⁹

The use of oral low-dose methadone as a coanalgesic to existing opioid therapy to treat neuropathic and complex pain in advanced cancer is a rather novel but promising mechanism-based approach. Preliminary reports implicate that the addition of low-dose methadone to a therapy with another opioid might improve pain control rapidly, is well tolerated, and reduces the risk of opioid-induced adverse effects.^10–13 However, methadone has a complex pharmacokinetic profile and even low doses can result in an opioid overdose.^14,15 Current studies provide scarce information on the effectiveness and risk of adverse effects of methadone, especially in terminally ill cancer patients using high-dose opioids.

Aim

The primary objective of this retrospective study was to examine whether addition of a small dose of oral methadone to an existing high-dose opioid therapy results in better pain control for patients with complex cancer-related pain, enrolled in specialized palliative care and close to end of life. A secondary objective was to study the safety of this add-on treatment regarding sedation, delirium, and respiratory depression.

Methods

All patients who received methadone at the Palliative In-Patient Care Unit at Stockholms Sjukhem Foundation from 2006 to 2013 were identified from medical records. The unit is specialized in end-of-life care with most patients suffering from advanced cancer.

Inclusion criteria were age 18 years or more, advanced cancer, and use of oral methadone in addition to another regular scheduled opioid. Patients who used methadone as a sole opioid, methadone only as-needed, or parentally methadone were not included.

Opioid doses were registered daily starting three days before (day −3) initiation of methadone (day 0). All other registrations were obtained each day during the first week following initiation of methadone. Data were obtained from the medical records concerning demographics (age, gender, and survival time), daily regular opioid dose and as-needed opioid doses, cancer diagnosis and presence of metastases, concurrent medications, and mechanisms of pain categorized as nociceptive, neuropathic, or mixed nociceptive–neuropathic.

Pain intensity and prevalence of delirium, sedation, and respiratory depression were independently assessed from the records by two physicians. When there was no or only minor descriptions of verbal complaints in the case records (conscious patients) or pain behavior (grimaces, etc. in unconscious patients), pain was graded as no/mild. Patients requiring occasional as-needed medication, who had some pain complaints or who exhibited more regular pain behavior (unconscious patients) were assessed as having moderate pain. A patient was assessed to have severe pain if in major distress and required as-needed medication regularly.

There was initially full concordance in 69%, minor differences (one level of difference on a single day) in 25% and major (two levels of difference or minor difference on more than one day) differences in 6% of the paired pain assessments and after discussions, the reviewers reached consensus for all patients.

The occurrence of delirium was registered by the assessors in accordance with DSM IV criteria using information from the medical records. The patients were categorized in two groups; no delirium or any degree of delirium. Also, sedation was assessed as no sedation or any degree of sedation. Respiratory depression was assessed as affecting respiratory frequency, and registered as a positive case, if there were any case record notes written by physicians or registered nurses, about clinical signs of respiratory depression (e.g., “breaths slowly,” or “only 8 breaths per minute”). The adverse effects were analyzed separately for patients surviving 14 days or less versus patients surviving more than 14 days.

All opioid doses were converted to morphine equivalent daily doses for daily routine opioids and as-needed opioids, respectively. Morphine equivalent doses were calculated according to guidelines from MD Anderson Hospital (Houston, TX).¹⁶

Statistics and ethical approval

Descriptive statistics presenting the median and range were used since data were not normally distributed. Wilcoxon signed-rank test was used to compare daily opioid doses. Chi-square test and Fisher's exact test were used for comparing adverse effects. Analyses were performed using SPSS (ver. 23.0.0.0).

Ethical approval was obtained from the Regional Ethical Review Board (Stockholm, Sweden).

Results

Four thousand two hundred thirty-three patients were admitted to the inpatient care unit between January 1, 2006 and December 31, 2013, of which 165 received methadone. Eighty patients were started with low-dose oral methadone in addition to a regular opioid treatment and were included in the study. The cancer diagnoses are presented in Table 1. The mean age was 68 years (median 68) and 51 (64%) patients were women. The median time of survival was 28 days (mean 37). The pain mechanisms were documented in 40 cases, of which 32 (80%) had neuropathic or mixed nociceptive–neuropathic pain.

Table 1.

Diagnoses

Cancer diagnoses
Prostate	10
Urogenital (other)	17
Pancreas	5
Gastrointestinal (other)	16
Lung	15
Breast	10
Skin	3
Hematological	1
Head and neck	1
Other	2
Stage of disease
Localized	1
Regional	12
Distant	67

Initial pain medication

The median total morphine equivalent dose (including as-needed doses, but excluding methadone) on the day of methadone initiation, day 0, was 290 mg (Table 2). Each patient was taking a median of 3 (range 0–5) adjuvant coanalgesic agents at the time methadone was initiated. Fifty-five percent were prescribed paracetamol, 54% nonsteroidal anti-inflammatory drugs, 46% steroids, 36% gabapentin or pregabalin, and 23% amitriptyline.

Table 2.

Daily Doses of Opioids (mg)

	Day −3	Day −1	Day 0	Day 1	Day 3	Day 7^a
Total morphine equivalent doses
Median (IQR)	255 (322)	255 (354)^*	290 (505)^*	275 (384)^**	255 (375)	250 (358)
Range	0–1440	0–1440	20–1900	0–1650	8–2300	15–4040
Mean (SD)	323 (311)	350 (325)	432 (395)	379 (355)	372 (382)	438 (672)
Regular morphine equivalent doses
Median (IQR)	200 (304)	220 (302)^*	220 (348)	240 (373)	240 (353)	198 (333)
Range	0–1300	0–1300	20–1300	0–1300	0–1400	0–4040
Mean (SD)	288 (289)	300 (293)	318 (294)	332 (316)	311 (353)	363 (546)
As-needed morphine equivalent doses
Median (IQR)	0 (40)	0 (60)	30 (108)^**	0 (60)^***	0 (79)	0 (60)
Range	0–300	0–480	0–1050	0–500	0–900	0–2100
Mean (SD)	35 (67)	49 (105)	114 (105)	47 (90)	61 (133)	71 (256)
Methadone doses
Median (IQR)			5 (5)	10 (10)	10 (5)	10 (10)
Range			3–30	0–30	5–30	5–30
Mean (SD)			7.3 (4.2)	10.5 (5.2)	11.4 (5.1)	12.5 (5.7)

Significance of change from preceding day in table.

p < 0.05

p = 0.001

***

p < 0.001.

Two outliers are included in the table (morphine equivalent daily doses 4040 and 3900 mg on day 7); however, these two values are excluded in the statistical analysis.

IQR, interquartile range; SD, standard deviation.

Thirty-eight percent of the patients used oxycodone, 36% morphine, 19% fentanyl, and 8% hydromorphone. Sixty-six percent of the patients used long-acting oral opioids, 15% received a continuous subcutaneous opioid infusion, and 19% used transdermal fentanyl.

Methadone doses

The median daily methadone dose the first day after start of methadone, day 1, was 10 mg (see Table 2 for details). The methadone dose was increased in 67%, decreased in 4%, and unchanged in 29% of the patients during the seven-day follow-up period. The median methadone dose on day 7 was 10 mg. The most frequent doses of methadone on day 1 were 10 mg (5 mg b.i.d.) in 46 (58%) and 5 mg (2.5 mg b.i.d.) in 24 (30%) of the cases.

Seventy-three of the patients used methadone for all seven days of the follow-up. Reasons for cessation of methadone were delirium (n = 2), increase in pain (n = 2), general deterioration (n = 1), unconsciousness (n = 1), and unknown (n = 1).

Changes in doses of other opioids

The total morphine equivalent doses, regular opioids, and as-needed opioids besides methadone, during the study period, are presented in Table 2. After exclusion of two extreme outliers (morphine equivalent daily doses 4040 and 3900 mg on day 7), the median total morphine equivalent dose on day 7 was 245 mg (interquartile range 323, mean 347, range 0–2000).

The median total morphine equivalent opioid dose increased from day 1 to 0 (p = 0.007), was reduced day 1 (p = 0.001), and then gradually decreased to a similar level as before addition of methadone.

Improvement of pain

On day 0, 6%, 30%, and 64% of patients were assessed to have no/mild, moderate, and severe pain, respectively. The corresponding numbers after one week were 63%, 25%, and 13% (p < 0.001) (Fig. 1). Eighty percent of patients were assessed to have improved pain control on day 7 compared with day 0 (p < 0.001).

FIG. 1.

Assessment of pain.

Adverse effects

The proportions of patients assessed to be sedated and/or delirious increased from day 0 to 7 (sedation: day 0 23%, day 7 54%; delirium: day 0 19%, day 7 47%). This increase was more pronounced in the group surviving 14 days or less compared with patients with longer survival time (Table 3). Although about 80% of the patients with short survival were sedated or delirious, the percentage of patients with severe symptoms was low: 17% for sedation and 21% for delirium.

Table 3.

Adverse Effects

	Survival ≤14 days		Survival >14 days
	Day 0	Day 7	Day 0	Day 7
Sedation (%)	29	79	20	45^*
Delirium (%)	25	79	16	34^**

Significance of difference between survival groups.

p < 0.01

p < 0.001.

No patient was assessed to have respiratory depression.

Discussion

We observed that the addition of a low dose of oral methadone resulted in improved pain control in patients with difficult cancer-related pain treated with high-dose opioids. Our results support previous findings suggesting that low doses of methadone may be of use when added to regular opioid therapy in patients with complex cancer-related pain.

Pain was reduced in 80% of our patients, which agrees with the results of Wallace et al. who studied 20 patients with uncontrolled moderate to severe cancer pain in an outpatient setting and observed improved pain control in 75% of the patients at one-month follow-up.¹⁰ Courtemanche et al. reported that 49% of patients responded with a decrease in pain during the first week after methadone initiation, whereas a further increase of methadone doses gave no further pain reduction.¹³ Whether this additive pain-relieving effect of low doses of methadone is due to NMDA receptor antagonism, opioid receptor agonism, or other mechanisms is not clearly understood and warrants further studies.

The initial doses of methadone in other studies varied between 2.5 and 10 mg/day.^10–13 Methadone doses were relatively stable over time in our patients and the median daily dose of methadone was unchanged at 10 mg daily. The stable low doses of methadone and decreased or unchanged regular opioid doses together with a clinical significant decrease in pain intensity highlight the interesting effects of add-on methadone therapy.

As patients approach end of life, several adverse symptoms are frequent. Sedation, delirium, and respiratory depression could in our study be due to methadone initiation and subsequent opioid overdose, to the dying process or to both. Our data regarding sedation and delirium were therefore dichotomized into two groups, patients with 14 days or less or more than 14 days of survival, respectively. The prevalence of sedation and delirium increased in all patients regardless of time of survival, but was significantly more pronounced in the group with the shortest survival. The prevalence of adverse symptoms was higher in our study as compared with the studies by Wallace et al.¹⁰ and Courtemanche et al.,¹³ which could be explained by higher median starting doses of methadone in our patients, more advanced disease, differences in definitions of categorizing a symptom as present, or a combination of these factors.

Respiratory depression from opioids is due to an imbalance between the nociceptive input and the effective opioid dose resulting in an inhibition of the respiratory center. Pain itself stimulates the respiratory drive.^17,18 In our study, respiratory depression was not associated with the use of low-dose oral methadone. This argues that the addition of a low dose of methadone, in a setting where the patient is carefully monitored by the physician in charge, is safe.

We recognize some strengths and limitations in our study. We included patients primarily in end-of-life care, an area of research with inherent difficulties, and the use of low doses of methadone seemed to be clearly effective in this subset of patients. We analyzed data from a relatively high number of patients and obtained information daily during seven days after initiation of methadone. We were also able to identify all patients who had received methadone, thereby, ensuring no missing data. A standardized protocol for evaluation of all patients together with independent assessment by two physicians increased the reliability of our findings.

Limitations include the retrospective study design with its inherent assessment of pain and adverse effects from medical records. In the absence of systematic numeric pain ratings, we needed to interpret the case records, according to a predefined protocol, as described in the Methods section. Up to 4 in 10 people suffer from delirium at the very end of life.¹⁹ Already in 1999, Jordhoy et al. demonstrated that compliance in completing health-related quality of life (HRQL) questionnaires was good up to one month before the patient's death; but in the final weeks it was found to drop substantially,²⁰ mainly due to debilitation, delirium, and lowered levels of consciousness. Thus, we do not have access to validated assessment tools for the immediately dying, as any tool or questionnaire is only validated in a given context.

Neither VAS (visual analogue scales) nor NRS (numerical rating scales) are validated in persons with delirium. Therefore, a study protocol that requires assessments with the aid of VAS or NRS would exclude most of the dying patients, the very patients in focus of our interest. For this reason, we developed an assessment scale for retrospective use, and it proved to be a feasible way of pain assessment. Furthermore, when the aim is to address experiences met in dying patients, a retrospective design can be a natural first step of research.

Results from retrospective studies can then be used to better plan and target later prospective studies. Additional limitations include the fact that the indications for start of methadone were at the physician's discretion and not standardized, and only the physiological aspects of the pain mechanisms were classified. The impact of possible social,²¹ psychological, or existential pain components²² were not registered. Finally, the study design was observative and included no comparative group.

Conclusion

Addition of low-dose oral methadone to regular opioid treatment in cancer patients with complex pain close to death resulted in a rapid decrease of observed pain intensity. There was an increased risk for sedation and delirium, especially in the group of patients with short survival time. The observations suggest that low-dose methadone therapy contribute to pain relief in some patients with complex cancer pain at the end of life, and it's use should be tested in controlled trials. Future studies could build on our findings to further understand and utilize add-on therapy with methadone.

Footnotes

Acknowledgments

This work was supported by the Stockholm County Council (ALF project). The authors thank Lisa Lüning, MD, for her assessment of patient records.

Author Disclosure Statement

No competing financial interests exist.

References

Portenoy

: Treatment of cancer pain. Lancet, 2011; 377:2236–2247.

Caraceni

, Hanks

, Kaasa

, et al.: Use of opioid analgesics in the treatment of cancer pain: Evidence-based recommendations from the EAPC. Lancet Oncol, 2012; 13:e58–e68.

van den Beuken-van Everdingen

, Hochstenbach

, Joosten

, et al.: Update on prevalence of pain in patients with cancer: Systematic review and meta-analysis. J Pain Symptom Manage, 2016; 51:1070–1090.e1079.

Portenoy

, Foley

, Inturrisi

: The nature of opioid responsiveness and its implications for neuropathic pain: New hypotheses derived from studies of opioid infusions. Pain, 1990; 43:273–286.

Rayment

, Hjermstad

, Aass

, et al.: Neuropathic cancer pain: Prevalence, severity, analgesics and impact from the European Palliative Care Research Collaborative-Computerised Symptom Assessment study. Palliat Med, 2013; 27:714–721.

Fitzgibbon

, Loeser

(eds): The perception of pain. In: Cancer Pain Assessment, Diagnosis and Management. Philadelphia, PA: Wolters Kluver/Lippincott Williams & Wilkins, 2010, pp. 10–16.

Sotgiu

, Valente

, Storchi

, et al.: 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; 60:284–290.

Falk

, Bannister

, Dickenson

: Cancer pain physiology. Br J Pain, 2014; 8:154–162.

Davis

, Walsh

: Methadone for relief of cancer pain: A review of pharmacokinetics, pharmacodynamics, drug interactions and protocols of administration. Support Care Cancer, 2001; 9:73–83.

10.

Wallace

, Ridley

, Bryson

, et al.: Addition of methadone to another opioid in the management of moderate to severe cancer pain: A case series. J Palliat Med, 2013; 16:305–309.

11.

McKenna

, Nicholson

: Use of methadone as a coanalgesic. J Pain Symptom Manage, 2011; 42:e4–e6.

12.

Haughey

, Watson

, White

: Use of methadone as a coanalgesic: Response to McKenna and Nicholson. J Pain Symptom Manage, 2012; 43:e5–e6.

13.

Courtemanche

, Dao

, Gagne

, et al.: Methadone as a coanalgesic for palliative care cancer patients. J Palliat Med, 2016; 19:972–978.

14.

Nilsson

, Meresaar

, Anggard

: Clinical pharmacokinetics of methadone. Acta Anaesthesiol Scand Suppl, 1982; 74:66–69.

15.

Fredheim

, Moksnes

, Borchgrevink

, et al.: Clinical pharmacology of methadone for pain. Acta Anaesthesiol Scand, 2008; 52:879–889.

16.

Fisch

: Dosing strategies for oral methadone. In: Fisch

(ed): Cancer Pain Management. New York: McGraw Hill Medical, 2007, pp. 307–310.

17.

Borgbjerg

, Nielsen

, Franks

: Experimental pain stimulates respiration and attenuates morphine-induced respiratory depression: A controlled study in human volunteers. Pain, 1996; 64:123–128.

18.

Hanks

, Twycross

: Pain, the physiological antagonist of opioid analgesics. Lancet, 1984; 1:1477–1478.

19.

Hosie

, Davidson

, Agar

, et al.: Delirium prevalence, incidence, and implications for screening in specialist palliative care inpatient settings: A systematic review. Palliat Med, 2013; 27:486–498.

20.

Jordhoy

, Kaasa

, Fayers

, et al.: Challenges in palliative care research; recruitment, attrition and compliance: Experience from a randomized controlled trial. Palliat Med, 1999; 13:299–310.

21.

Eisenberger

, Lieberman

, Williams

: Does rejection hurt? An FMRI study of social exclusion. Science, 2003; 302:290–292.

22.

Strang

, Strang

, Hultborn

, et al.: Existential pain—An entity, a provocation, or a challenge?. J Pain Symptom Manage, 2004; 27:241–250.