Long-term Therapy Using Short Acting Opioids for Chronic Non-cancer Pain

Opioids can, and do, play a role in the modulation of pain.^1-3 Opioid therapy for chronic non-cancer pain appears to have gained in popularity,^4,5 if not acceptance, in the past decades but remains controversial.⁶ Indeed, Brennan, Carr and Cousins⁷ went so far as to conclude “Opioids remain the drugs of choice for the treatment of moderate to severe pain, regardless of etiology.” There are a variety of routes of administration including oral, buccal, transdermal, intravenous (IV), and intrathecal (IT). Oral opioids are perhaps the most frequently used in the clinical setting and may be conveniently classified as short acting (SA) such as immediate release, or long acting (LA) such as sustained released, controlled released, and extended release.

A number of ‘guidelines’ regarding long term opioid therapy have been proposed.^8-12 They often recommend the use of LA over SA opioids. It has always been assumed that LA opioids: (a) provide more consistent and stable serum levels, and therefore more stable analgesia, (b) enhance compliance secondary to reduced frequency of dosing, (c) are less likely to be ‘abused’ as they are not as often associated with euphoria, and (d) less likely to activate an ‘addiction’ process or pattern of abuse. The initial use of SA opioids to establish baseline requirements followed by a transition to LA opioids is often urged.^9-12

Recent issues of Practical Pain Management have highlighted the use of LA opioids in the treatment of chronic pain. Tennant13 outlines an approach for transitioning from SA to LA. He notes concern over the potential problem of excessive acetaminophen intake given its frequent use in combination with the SA opioids such as codeine, hydrocodone, oxy-codone, and propoxyphene. Four indications, including failure to control pain with eight or more doses per day, are outlined for converting from SA to LA. He states however, “The failure to control severe, chronic pain with short acting opioids invariably occurs in a patient who complains of severe, constant, persistent pain.” Sustained blood levels of an opioid, which is presumably associated with pain relief, is listed among the advantages of LA preparations. Schneider14 offers support for the use of LA opioids citing acetaminophen use, plasma levels, com-pliance, dosing frequency, euphoria and sleep as issues with SA opioids. Schneider also notes the common use of SA in addition to LA for “breakthrough” pain. Time of day, patient activity, weather, mood, life stresses are listed as possible sources of breakthrough pain.

Although proponents of the use of LA opioids assert their advantages,⁸ Chou et al,¹⁵ in a systematic review of studies comparing SA to LA, found the data to be inconclusive at best. One plausible reason for this apparent lack of benefit of LA over SA opioids may be based in the recognition that the efficacy of opioids appears to be related to a variety of factors other then their pharmacodynamic and pharmacokinetic properties. For example, age of the patient and type of pain (nociceptive or neuropathic),¹⁶ gender,¹⁷ history of substance abuse,¹⁸ cognitive functioning,19 and co-morbid psychopathology20 have each been shown to influence the analgesic effect of opioids in general.

One frequently overlooked area is that of conditioning and learning. Siegal and his colleagues21 have explored the role of conditioning factors, particularly classical conditioning, as they relate to the development of opioid tolerance. Opioid therapy is likely to continue when the ingestion of a drug is reinforced by the reduction of a negative state such as pain, anxiety, depression, and/or the onset of a positive state such as reduced pain, euphoria, sedation, or improved function. Stimuli, either external (exteroceptive) to the patient such as size, color, or shape of the pill, or internal to the patient (interoceptive) such as sense of well being, autonomic changes, may become associated with the drug that is producing these desirable states. By virtue of the classical conditioning process, these stimuli become capable of eliciting some or all aspects of the final drug-induced outcome. Stimuli associated with the onset of the drug-induced effect have been labeled as drug onset cues (DOCs) and those with the taking of the drug as self-administration cues (SACs). Thus, patients often insist that the ‘brown, square pill works better than the white, triangular one,’ even when they are similar compounds. It is these conditioned properties of opioids that may lead to positive expectations so often responsible for the well recognized ‘placebo’ response. Indeed, some 30-50% of the analgesic response to various drugs has been attributed to the placebo effect when studied in an ‘open-hidden’ paradigm.²²

The present study intended to extend the evaluation of SA opioids in the long term treatment of chronic non-cancer pain by examining a cohort of patients using SA opioids for several years. Furthermore, the possible role of conditioning factors was explored by seeking information regarding DOCs. The patients were ‘self-selected’ as a result of: (a) preferring SA opioids to previously trialed LA, or (b) satisfied with the results of SA opioids and not wishing to change.