The management of chronic cancer pain often involves the long-term administration of strong (i.e. pure mu-receptor agonist) opioids. Due to tolerance and / or cancer pain progression, dosage increasement is often necessary over time. Opioid rotation is a treatment strategy that can be applied in order to optimize analgesia and minimize side effects. Although concisely accounted for in the current guideline, literature support was scarce at time of writing due to the lack of randomized studies (2020, very low grade).

In recent years the administration of and rotation to methadone has become more common. A more profound embedding of this drug in the guideline is considered necessary from a clinical perspective, with concurrent revision of literature supporting opioid rotation including but not limited to methadone.

Summary of Findings

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PICO 1. Efficacy of opioid switch

_{1. Risk of Bias: serious. Inadequate/lack of blinding of participants and personnel, resulting in potential for performance bias, Inadequate sequence generation/ generation of comparable groups, resulting in potential for selection bias; Indirectness: serious. Due to the design of the study, the study made an indirect comparison of the intervention and control group. Imprecision: serious. Low number of patients.}

_{2. Risk of Bias: serious. Inadequate/lack of blinding of participants and personnel, resulting in potential for performance bias, Inadequate sequence generation/ generation of comparable groups, resulting in potential for selection bias Indirectness: serious. Due to the design of the study, the study made an indirect comparison of the intervention and control group. Imprecision: serious. Low number of patients.}

PICO 2. Efficacy of Methadone Rotation and Comparison Between Different Methods of Rotation to Methadone

Since none of the studies met the inclusion criteria, no quality of evidence (GRADE) and conclusions based on literature could be drawn.

Description of studies

For PICO 1, one study (Corli, 2019) was included that compared an opioid switch to no switch.

Corli (2019) conducted a post-hoc analysis from a multicenter, randomized, four-arm, controlled, phase IV clinical trial. They analyzed the impact of opioid switching in a cancer pain population treated with strong opioids for pain (N=498). Patients with advanced/ metastatic solid tumors were randomized in equal groups to receive either oral morphine (active comparator) or transdermal buprenorphine or oral oxycodone or transdermal fentanyl. Patients were eligible with persistent moderate to severe cancer pain [average pain intensity (API) in the last 24 h ≥4 points measured on a 0 to 10 Numerical Rating Scale (NRS) ranging from no pain to the worst imaginable pain] and the prescription of strong opioids never previously given.

Since this would lead to limited evidence, we decided to describe three additional studies (one systematic review and two additional non-randomized studies) in the summary of the literature, that did not meet the inclusion criteria. These additional studies describe further evidence on opioid rotation and the role of methadone and could therefore potentially support the recommendation. These studies will not be graded for their level of evidence (no clinical relevance is assessed). Important study characteristics and results are summarized in table 2. The assessment of the risk of bias is summarized in the risk of bias tables (under the tab ‘Evidence tabellen’).

Good (2014) conducted a systematic literature search for randomized controlled trials (RCTs) published post the 2007 Cochrane review of methadone in cancer pain. They included four randomized trials (272 participants). Two RCTs (Mercadante, 2008; Lauretti, 2013) compared the efficacy and safety of methadone with placebo or active control and two studies investigated rotation to methadone from other opioids (Moksnes, 2011; Cubero, 2010). The studies used different routes of administration, dosing, initiation, and titration of methadone and distinct pain scoring tools. In this analysis, Lauretti (2013) was excluded as they administered methadone epidurally, which was not relevant to the current research question.

In addition, two non-randomized studies were described (Mercadante 2001; 2012) that were not included in the systematic review by Good. They described a switch from an opioid to methadone in patients with cancer related pain. Table 3 depicts further details regarding the studies.

Table 3. Characteristics of included studies

_{*For further details, see risk of bias table in the appendix}

Results

PICO 1: Efficacy of Opioid Switch

Pain intensity (crucial)

Corli (2019) reported that 45 patients switched due to previous analgesic inefficacy. In those patients, the mean API score (measured on NRS 0-10) ranged from 5.0 (± 2.0) to 3.7 (± 1.6) before and after the switches, thus decreasing on average by 31.2%. The worst pain intensity (WPI) varied from 6.4 (± 2.6) to 5.4 (± 1.7) with a 13.3% decrease. Pain reduction was adequate (defined as decrease >30% of API) after 51.45% of switches. Pain reported was mostly breakthrough pain (46.8%), or neuropathic or mixed pain (24.1%).

Adverse effects

Corli (2019) reported that 23 patients switched due to opioid toxicity.

For each adverse event, the responders, poor responders and non-responders after opioid switch were reported (Table 4). Responders were defined as adverse drug reaction (ADR) disappeared or decreased ≥2 points as reported on Therapy Impact Questionnaire (TIQ). Poor responders had a decrease of 1 point and non-responders had an unchanged or worse intensity for ADRs.

Table 4. Responses after switch for adverse events (Corli, 2019)

In summary, there were ≥50% of responders among patients with vomiting and confusion, whereas non-responders prevailed in the case of constipation and dry mouth. The control of opioid side effects was adequate (responders) after switching in 43.5% of patients.

Quality of life

Not reported.

Patient satisfaction

Not reported.

PICO 2a: Efficacy of Methadone Rotation

Pain intensity (crucial)

Mercadante (2008) showed no clinically relevant difference in pain intensity among the groups. Mean pain intensity after 4 weeks (scale 0-10): 2.5 (morphine), 2.4 (fentanyl) 3.4 (methadone). No standard deviations were reported. Pain reported was a mix of nociceptive-neuropathic pain.

Cubero (2010) reported a lower pain intensity (numerical scale 0-10) after switching to methadone compared to baseline, although adding paracetamol did not enhance the effect.

Both groups (methadone rotation with and without paracetamol) went from score 5.0 at baseline to 3.5 after 7 days.

Pain intensity scored with the Faces pain scale gave similar results. Both groups went from score 6 at baseline to 4 after 7 days. Pain was mostly non-neuropathic. No standard deviations were reported.

Mercadante (2012) retrospectively observed that in 267 out of 345 patients (77.3%) substitutions with methadone were considered successful, presenting a decrease in pain intensity and/or symptoms intensity expressed as DS of more than 33%. No average pain scores were reported. The majority of patients had mixed nociceptive-neuropathic pain.

Mercadante (2001) reported a clinically relevant reduction in pain intensity in patients who switched to methadone. VAS scores (scale 0-10) went from 6.15 (95% CI 5.5 to 6.7) at time of opioid switching from 3.06 (95% CI 2.5 to 3.6) at time of stable opioid dose. Patients had most often somatic or mixed somatic-neuropathic or somatic-visceral pain.

Adverse effects

Mercadante (2008) reported several adverse effects for the comparison of methadone with morphine and fentanyl.

Adverse effects were measured using a scale from 0 to 3 (not at all, slight, a lot, severe). Nausea, vomiting, drowsiness, constipation, and confusion were similar across groups.

Central side effects (such as confusion and drowsiness) were slightly more pronounced with methadone and morphine than with fentanyl.

Distress score (sum of symptom intensities) increased during the first two weeks with methadone, but these symptoms did not require discontinuation of treatment and no differences in consumption of drugs used to manage opioid-induced adverse effects and non-opioid-analgesics were found.

Cubero (2010) reported adverse effects for the comparison of methadone with and without acetaminophen:

After switching from morphine to methadone, side effects decreased.

Significant reduction in constipation (P < .001) and dry mouth (P = .03) were observed after 7 days. No absolute data were available, and clinical relevance could not be judged.

Mercadante (2001) reported that in the 32 patients switching because of uncontrolled pain and morphine-related adverse effects, significant improvement was found in nausea and vomiting (P < .03), constipation (P < .001), and drowsiness (P < .01), but a significant increase in the methadone dose of an average of 20% (P < .004) was required. No absolute data were available, and clinical relevance could not be judged.

Quality of life

Mercadante (2008) used the Spitzer QoL Index rated on a Likert 3-point scale (0–2) in five areas (activity, daily life, health perceptions, social support, and behavior). There was no difference in QoL among the groups. QoL remained stable during 4 weeks of follow-up. No absolute data were available, and clinical relevance could not be judged.

Cubero (2010) used a standardized QoL questionnaire for cancer patients (QLQ-C30 version 3.0) before and after completion of the intervention period. QoL improved significantly after switching from morphine to methadone. There was no enhanced effect in the group with add-on paracetamol. No absolute data were available, and clinical relevance could not be judged.

Patient satisfaction

This outcome was not explicitly reported as a score in the studies. However, Cubero (2010) reported that 71% of patients preferred methadone over morphine.

PICO 2b: Comparison Between Different Methods of Rotation to Methadone

Pain intensity

Moksnes (2011) reported mean pain intensity on Brief Pain Inventory (BPI, 0-10) at baseline and after 14 days.

The Stop-and-Go group reported 5.4 at baseline and a slight increase after 14 days.

The 3-Day Switch group reported 5.5 at baseline and a decrease after 14 days. No absolute change in scores was available, and clinical relevance could not be judged.

Quality of life

Not reported.

Adverse effects

Moksnes (2011) reported adverse effects for the comparison of Stop-and-Go versus 3-Day Switch for methadone rotation.

No significant differences in side effects such as drowsiness, nausea, loss of appetite, or dry mouth were observed.

The mean differences between groups day 3 were for drowsiness 0.0 (95% CI -1.3–1.6), for nausea 0.1 (95% CI -1.0 to 1.0), for loss of appetite 1.2 (95% CI -1.1 to 3.5) and for dry mouth 0.6 (95% CI -1.2 to 2.3). This differences were not clinically relevant. Regarding QTc prolongation (risk of cardiac arrhythmias): in the Stop-and-Go group the QTc interval increased, while in the 3-Day Switch the QTc interval decreased.

A systematic review of the literature was performed to answer the following questions:

What is the effect of opioid rotation or switch compared to no opioid rotation or switch in patients with pain due to cancer (treatment)?

Table 1. PICO 1

What is the effect of opioid rotation or switch to methadone compared to adding methadone to an opioid in patients with pain due to cancer (treatment)?

Relevant outcome measures

The guideline panel considered pain intensity and adverse events as a critical outcome measure for decision making; and quality of life and patient satisfaction as an important outcome measure for decision making.

A priori, the guideline panel did not define the outcome measures listed above but used the definitions used in the studies.

The guideline panel defined the following as a minimal clinically (patient) important difference:

• Adverse effects: 10% difference.
• Pain intensity (scale 0-10): MD <-1 or > 1.
• Quality of life: SMD < -0.5 or > 0.5.
• Patient satisfaction: SMD < -0.5 or > 0.5.

Search and select (Methods)

A systematic literature search was performed by a medical information specialist using the following bibliographic databases: Embase.com and Ovid/Medline. Both databases were searched from 2000 to 2024 for systematic reviews, RCTs and observational studies. Systematic searches were completed using a combination of controlled vocabulary/subject headings (e.g., Emtree-terms, MeSH) wherever they were available and natural language keywords. The overall search strategy was derived from three primary search concepts: (1) cancer; (2) pain; (3) opioid rotation. Duplicates were removed using EndNote software. After deduplication a total of 395 records were imported for title/abstract screening. Initially, 26 studies were selected based on title and abstract screening. After reading the full text, 25 studies were excluded (see the exclusion table under the tab ‘Evidence tabellen’), and 1 study was included.