Watchful Dose = morphine or equivalent dose exceeding 200 mg/day
Some patients may require higher doses of opioids (e.g., patients who are benefiting from opioids but have developed tolerance), but based on existing RCTs, the majority of patients with CNCP will respond at doses up to the equivalent of 200 mg/day of morphine.
1. Considerations before Dose Exceeds 200 mg/day
Before prescribing over 200 mg/day, consider:
1.1 Reassessment of the pain problem
1.1.1 Diagnosis or multiple diagnoses (co-morbid disorders)
- Is diagnosis (es) accurate?
- Is opioid effective for the patient’s diagnosis(es)? (See Recommendation 4 for an overview of evidence of opioid efficacy.)
- Is further investigation and/or consultation required?
- Are non-opioid treatment options available?
- Is there an inadequately treated mental health disorder?
1.1.2 Patient’s response to opioids
- Has the patient shown appropriate opioid effectiveness (i.e., improved function or at least 30% reduction in pain intensity) in response to the dose increases to date? (Opioids have a graded response with the greatest benefit at the lowest doses.) If response has been insignificant, continuing to increase the dose will be futile. Switching or discontinuing the opioid could be considered.
- Are there indications of increased medical complications and adverse effects? Some complications, i.e., opioid-induced hyperalgesia, cognitive impairment (attentional performance) and hypogonadism occur more frequently with higher doses (also see Recommendation 5).
1.1.3. Risk of misuse
- Is there any indication of aberrant drug-related behaviours?
2. Monitoring Doses Exceeding 200 mg/day
If prescribing over 200 mg/day, monitor patients more frequently for opioid effectiveness, medical complications, adverse effects and risks.
R10. Summary of Peer-Reviewed Evidence
1. Evidence of effectiveness and adverse effects from randomized controlled trials
The systematic review update described in Part A: Literature Search Methods included 62 randomized trials, of which 25 employed a titration or fixed scheme to achieve optimal analgesia (Furlan unpublished 2010). The maximum, minimum, and average daily doses of morphine equivalents are shown in Table B-10.1 below.
Randomized trials of tramadol or codeine are not shown Table B-10.1 because there is a maximum pre-established daily dose of 400 and 600 mg respectively. Elderly patients (>75 years of age) should receive maximum of 300 mg of tramadol per day (Pascual 2007). Trials of transdermal fentanyl are not shown because they are not recommended for opioid-naive patients, and it is commonly used as a second-line opioid; therefore the usual doses of transdermal fentanyl are dependent on the doses of the first-line opioid. In many cases patients with extremely high doses of other opioids are switched to transdermal fentanyl in an attempt to decrease the adverse effects and improve analgesia. Trials of transdermal buprenorphine were excluded because the conversion rate to morphine equivalent is not well established.
Table B-10.1 Morphine Equivalents for Strong Opioids used in Randomized Controlled Trials
MEQ = morphine equivalent, NR = not reported.
2. Concerns regarding high daily dose of opioids from observational studies
The potential for adverse psychological and physical effects, the potential for misuse, and questionable efficacy are all factors that should be considered in limiting the dose and increasing the frequency of follow-up visits. Some studies reported safety concerns or questionable efficacy of higher daily doses of opioids.
Rowbotham and Lindsey reported on a long-term open label study where study patients were discouraged from exceeding a total of 360 mg/day MEQ. Twenty-nine patients entered the study, and interestingly there was a sex difference with men reaching both a higher dose (282 compared to 150 mg/day), and showing greater dose escalation (Rowbotham 2007).
2.1. Hypogonadism related to higher daily dose
In 2003, Rajagopal and Bruera studied 20 male patients with cancer-related chronic pain who were disease-free for at least one year and all patients were consuming at least 200 mg/day MEQ. They found marked central hypogonadism and sexual dysfunction in this population (Rajagopal 2003). They reported on a case of a cancer survivor who showed improvement in sexual function after reduction of chronic high-dose MEQ daily dose from 690 mg to 20 mg (Rajagopal 2003).
2.2. Poor outcomes in population receiving higher daily dose
Rome et al. reported the outcomes of a chronic non-cancer pain rehabilitation program according to opioid use status at admission (Rome 2004). They stratified the participants into non-opioid group (n=221), low dose (< 41 mg/day) opioid users (n=71), and high dose (>41 mg/day, average 137.48 mg/day) opioid users (n=64). The outcomes at discharge showed that patients taking higher doses reported significantly greater catastrophizing and greater pain severity than the non-opioid group. There were no significant pre-treatment differences between the groups regarding demographics, pain duration, treatment completion or all outcome variables including pain severity.
Two recently published studies conducted in the workers’ compensation population showed similar results. Webster et al. showed that mean disability duration, mean medical costs, risk of surgery and late opioid use increased with higher MEQ amounts. Those who received more than 450 mg were on average disabled 69 days longer than those who received no opioids (Webster 2007). Franklin et al. showed a statistically significant correlation that the receipt of more than 150 mg/day of morphine equivalent doses was associated with doubling of one-year disability risk (Franklin 2008).
2.3 Adverse events more commonly observed at higher daily doses
Pascual et al. reported on an open-label study of the safety and effectiveness of long-term therapy with extended-release tramadol in the management of 919 patients with non-malignant pain (Pascual 2007). Adverse events were noted to begin more commonly at average daily doses of 300–399 mg/day or > 400 mg, than at lower doses. Two patients experienced seizures during the study (one serious and one non-serious), and both events occurred at a dose of 400 mg/day.
In a randomized trial of morphine compared to placebo for patients with neuropathic pain, attentional performance was assessed with the “d2-test”, measuring vigilance over a 20-minute time period. The dose of morphine was titrated to at least 70 mg/day and at highest 300 mg/day. The results showed that the reduction of attention during morphine compared to placebo was more pronounced when a high dosage was taken (attentional deficit and dose: r = 0:73, P<0:05) (Huse 2001).
2.4 Conflicting evidence regarding the dose relationship between opioids and sleep apnea
Walker et al. report on a retrospective study comparing 60 patients taking chronic opioids with 60 patients not taking opioids to determine the effect of opioid dose on breathing patterns during sleep. After controlling for BMI, age, sex, there was a dose-response relationship between morphine-equivalent dose and apnea-hypopnea, obstructive apnea, hypopnea and central apnea indexes. They concluded that there is a dose-dependent relationship between chronic opioid use and the development of a peculiar pattern of respiration consisting of central sleep apnea and ataxic breathing (Walker 2007).
One observational study of chronic pain patients on opioid therapy was designed to assess whether a dose relationship exists between methadone, non-methadone opioids, benzodiazepines and the indices measuring sleep apnea. They included all consecutive (392) patients on around-the-clock opioid therapy for at least 6 months with a stable dose for at least 4 weeks. Available data were analyzed on 140 patients. The apnea-hypopnea index was abnormal (≥5 per hour) in 75% of patients (39% had obstructive sleep apnea, 4% had sleep apnea of indeterminate type, 24% had central sleep apnea, and 8% had both central and obstructive sleep apnea); 25% had no sleep apnea. They found a direct relationship between the apnea-hypopnea index and the daily dosage of methadone (P= 0.002) but not to other around-the-clock opioids. They concluded that sleep-disordered breathing was common in chronic pain patients on opioids. The dose-response relationship of sleep apnea to methadone and benzodiazepines calls for increased vigilance (Webster 2008).
Another study reported on 6 cases of patients receiving opioids for CNCP for more than 6 months referred to a sleep study because of excessive daytime sleepiness (Allatar 2009). All six cases had a diagnosis of central sleep apnea. Three patients also had obstructive sleep apnea. The opioid doses were 120, 230, 262, 300 (two) and 420 MEQ per day.
2.5 Opioid-induced hyperalgesia related to higher daily doses
Cohen conducted a study on 355 patients on a steady regimen of opioids who volunteered to receive a standardized subcutaneous injection of lidocaine prior to a full dose of local anesthetic for a scheduled interventional procedure. Before and after the injection, they were asked to rate pain and unpleasantness. Subjects were stratified into 6 groups based on the dose of opioids they were taking. A group of 27 volunteers who had no pain and no analgesics were also injected. Both opioid dose and duration of treatment directly correlated with pain intensity and unpleasantness scores. Baseline pain intensity and female genders were also predictive of responses. The results of this study are in agreement with experimental studies of enhanced pain perception in subjects receiving opioid therapy (Cohen 2008).
3. Evidence from other systematic reviews, opinion papers, and clinical practice guidelines
In a recent review, Ballantyne and Mao indicated that doses higher than 180 mg of MEQ/day have not been validated in clinical trials and should be considered excessive (Ballantyne 2003).
In a recent editorial in JAMA, McLellan and Turner call for physician responsibility in prescribing opioids because of the direct relationship between amount of prescriptions and public health threats from prescription diversion. They advise physicians that opioid doses should be
re-evaluated regularly because analgesic response has been shown to wane at longer intervals (McLellan 2008).
The 2009 “Clinical Guidelines for the Use of Chronic Opioid Therapy in Chronic Noncancer Pain” (The American Pain Society and American Academy of Pain Medicine) proposed by panel consensus, a reasonable deﬁnition for high-dose opioid therapy as >200 mg daily of oral morphine (Chou 2009).
4. Opioid-receptor genotype associated with higher opioid dose required to achieve pain relief
Analgesic efficacy of mu-acting drugs has been linked to the 118>G single nucleotide polymorphism (SNP) of OPRM1, the gene encoding the mu-1 receptor. The frequency of the variant G allele varies from 10% to 48% depending on the population studied. Studies conducted in cancer pain show that patients carrying the GG (homozygous variant) genotype require much higher opioid doses to achieve pain relief. In AA patients the daily morphine dose was 112 mg, in AG patients the dose was 132 mg and in GG patients the dose was 216 mg. All three groups achieved the same pain relief (Reynolds 2008.).