Opioid dose escalation

Apart from opioid-related side effects, the major problem with long-term opioid therapy is progressive dose escalation. Many societies are concerned with limiting opioid dose escalation in individuals and in the community, often through legislation, usually to control the adverse social effects of opioids, including addiction and criminality.

The major causes of opioid dose escalation are:

• decreased opioid analgesic efficacy:

- opioid-induced neuroadaptation:

• opioid-induced hyperalgesia (OIH).

- increased pain:

• development of chronic pain (e.g. central sensitization, neuropathic pain);

• breakthrough pain (intercurrent illness or disease progression).

• increased opioid demand due to maladaptive behaviors:

- opioid reward-center effects;

- addiction;

- opioid diversion (pseudoescalation);

- associative tolerance (or hyperalgesia):

• conditioned response: opioid nocebo effect.

• effects of opioid dependence and withdrawal:

- neuroadaptation and behavioral factors;

- motivation to continue or increase opioid dose is avoidance of withdrawal symptoms.

In patients with CNCP, the most frequent cause of opioid dose escalation is inadequate analgesia due to disease progression or the development of chronic pain, OT, or OIH. Maladaptive opioid-use behaviors, such as addiction, are far less common, occurring in fewer than 10 percent (3.2-18.9 percent) of patients treated for CNCP108 and withdrawal symptoms are also infrequent.60 When considering opioid dose escalation in the treatment of chronic pain, the major issues are how frequently the problem occurs (prevalence), the rate of escalation and the final or ceiling dose, as well as causes, modifying factors, and treatments.

Most patients treated with opioids for chronic or cancer pain do not exhibit significant dose escalation, in contrast to those treated for addiction in which escalation seems to be more problematic.109'110 Only 10-30 percent of patients on long-term (nine months to five years) opioids for CNCP required significant dose escalation because of inadequate analgesia.23,26,91,111112[II], 19,22, 109,113 Fewer patients required dose escalation with transdermal buprenorphine compared with other opioids.26

The rate of dose escalation may be a significant factor in managing long-term opioid therapy for CNCP. The opioid escalation index (OEI), defined as the mean increase in dose compared with the starting dose (as a percentage or in milligrams), is used to measure dose escalation in cancer pain research.114

A crude estimate of the opioid dose escalation rate (ODER) for all opioids in the treatment of CNCP is 0.5 percent per day.26' 115 116117

In a retrospective chart review of 288 patients with CNCP commenced on an oral morphine equivalent dose of 50 mg per day, the average ODER was 1.8 percent (0.88 mg of oral morphine) per day over 15 months.115 The average ODER with transdermal fentanyl was 0.25-0.42 percent (0.42-1.32 mg oral morphine equivalent) per day (over 12-18 months); however, with transdermal buprenorphine, the ODER was only 0.10 percent, approximately half the rate of fentanyl and 1/15th that of oral morphine.26,116 The ODER for morphine, fentanyl, or buprenorphine in the treatment of cancer pain was approximately twice that seen in CNCP.26,118

In older patients, the ODER was approximately half the rate of younger patients. The ODER was higher in the treatment of nociceptive pain compared with neuropathic pain, except in the elderly where there was no difference.115 In summary, the ODER was higher when treating cancer pain compared with CNCP. In contrast, the ODER was lower in the elderly, in neuropathic pain or using transdermal buprenorphine.

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