Fifty-five patients stopped the first opioid for intolerable side effects (25), ineffectiveness (29), or other reasons (1); 52 received a second prescription of an opioid. The distribution of the drugs prescribed as second choice were methadone (15), time-release morphine (11), time-release oxycodone (9), transdermal fentanyl (5), levorphanol (6), hydrocodone (3), and oxycodone (3). The doses and mean duration of the prescription of the different opioids prescribed as the second choice are shown in Table 3. Among the 25 patients who stopped the first opioid for intolerable side effects, 10 stopped the second opioid for the same reason. For the 29 patients who stopped the first opioid prescribed for ineffectiveness, the second opioid was effective in 10 cases. The second opioid prescribed to 52 patients was effective for 16 patients, stopped for intolerable side effects in 14 cases, for ineffectiveness in 20 cases, and for other reasons in 2 cases.
Distribution, doses, and duration of the third, fourth, and fifth opioids prescribed are shown in Table 3. The third opioid prescribed to 30 patients was effective for 12 and was stopped for intolerable side effects in 9 and for ineffectiveness in 9 cases. The fourth drug, prescribed to 18 patients, was effective for 10 patients and was stopped for side effects in 2 and for ineffectiveness in 6. The fifth opioid, prescribed to seven patients, was effective for one and was stopped for side effects in four and for ineffectiveness in two. Figure 1 shows the percentage of patients who benefited from the different drugs. Most of the patients who stopped the first opioid for side effects also stopped the other opioids tested for side effects. In the same way, the majority of the patients who stopped the first opioid for ineffectiveness also stopped the other opioids tested for the same reason. The order in which the opioids were prescribed had no influence on efficacy.
We compared the efficacy and the tolerability of the different drugs prescribed. The tolerability was evaluated by using the number of side effects that occurred after the first prescription and expressed as the ratio between the number of side effects with a score greater than 30 and the total number of side effects. The efficacy was calculated as the ratio between the number of patients for which the drug was effective during five different prescriptions and the total number of prescriptions. With this method of comparison, we found that transdermal fentanyl was the most tolerated and timed-release morphine was the most effective.
At the end of a trial of five different opioids, 16 patients (19%) did not find an effective opioid therapy. Their diagnoses were: back pain (4), headache (3), neuropathy (3), joint pain (2), RSD (2), fibromyalgia (1), and visceral pain (1).
During this study, we noted only one case of addiction and no case of tolerance. The addiction occurred in a woman, 44 yr old, with compulsive drug use and a history of alcohol abuse. She suffered from chronic headaches and was treated with methadone. She was acquiring opioids from four other pharmacies and self-medicating.
The population of patients who suffer from chronic pain is diverse and the diagnoses varied. In our retrospective chart review, most patients were women, and the most common diagnoses are low back, neuropathic, and joint pain. There are conflicting reports on the responsiveness of neuropathic pain to opioids (8). In a study of 100 patients, 53 with neuropathic pain, Zenz et al. (4) reported good efficacy of opioids. In a study by Bouckoms et al. (7), neuropathic pain did not respond to opioids, and they concluded that neuropathic pain should not be treated with these drugs. Twenty patients suffered from neuropathic pain in our population; 17 (85%) had adequate pain relief with an opioid therapy. The other controversial indication is the efficacy of opioids for headaches (9,10). In our study, five patients suffered from intractable headaches, two of whom benefited from opioid therapy.
The individual variability in the response to different opioids that interact on the same μ-opioid receptor has been reported (11,12). Several hypotheses can be proposed to explain this variability. A genetic difference in sensitivity to opioids has been demonstrated in animal studies. The genetic difference is not the same for each receptor, such as the μ and κ receptors, which are under independent genetic control. Therefore, the sensitivity of a specific drug toward a particular receptor can vary independently of the other receptor subtypes (13). Another explanation could be the difference in intrinsic efficacy among opioids. The relationship between receptor occupancy and drug effect may vary for drugs that interact at the same receptor. The opioids as a function of their efficacy may explain the incomplete cross-tolerance between two μ-opioid agonists (14,15). The induction and maintenance of inflammatory pain, ischemic pain, and neuropathic pain involve the N-methyl-D-aspartate receptor. This receptor, which is activated by glutamate, is associated with a reduction in sensitivity to opioids (16).
The pharmacokinetic difference among drugs is also an important factor (17). The oral bioavailability differs among opioids and can be responsible for the interindividual efficacy of the opioids (18). Morphine is converted in the liver into two different metabolites: morphine-6-glucuronide and morphine-3-glucuronide, both of which and are present in abundance after chronic oral delivery and play a significant role in mediating the analgesia and side effects (19). Fentanyl is also metabolized in the liver and to a lesser degree in the kidneys. There is a predominant role of cytochrome P450 3A4 in the primary hepatic fentanyl metabolism. Intestinal and hepatic first pass metabolism may be subject to individual variability in P450 3A4 expression and differences in efficacy (20). These different mechanisms that interact in the nociception process may explain why some patients with similar mechanisms of pain respond differently to the same drug. Even though the mechanism of the pain is similar, individual pharmacodynamic and pharmacokinetic differences exist (16).
Another controversy surrounding the use of chronic opioid therapy in noncancer pain is the problem of addiction and tolerance (7,21). As the problem of addiction is serious and concerns the physician, the prevalence varies according to studies. In a study of 11,882 patients who received a narcotic preparation, Porter and Jick 1 related only four cases of addiction. Kouyanou et al. (23) reported in a study of 125 patients with chronic pain a prevalence of abuse of 8%. Bouckoms et al. (7) reported a 24% incidence of addiction in patients with chronic nonmalignant pain treated with long-term oral narcotic analgesics. The difference between these results may be a result of differences in the definition of addiction. It has been suggested that the Diagnostic and Statistical Manual III-R criteria for substance abuse cannot be used to diagnose addiction in pain patients because five of the nine criteria refer only to physical dependency and tolerance, which can occur in long-term opioid treatment (21,24). A new definition is necessary and may include loss of control over drug use, compulsive drug use, and continued use despite harm (24). Furthermore, it is necessary to differentiate between addiction and pseudoaddiction. Pseudoaddiction is a term that has been applied to patients who develop behaviors reminiscent of the addict as a result of iatrogenic undertreatment of pain (21,24). According to these criteria, we find only one case of addiction (1%) in a patient with a history of substance abuse.
Pharmacologic tolerance is defined as the need for increasing doses to maintain drug effects. However, the dose escalation can be attributed to tolerance only in the absence of other reasons for increasing pain, which includes increasing nociception and varying psychological or cognitive factors (21,24). Patients who are given an opioid therapy often achieve a plateau of stable dosing that extends for a long period (1,6). It is generally agreed that absolute tolerance to the analgesic effects of opioids does not occur (21,25). We noted no case of pharmacological tolerance.
We deliberately decided in our practice not to systematically treat side effects because a tolerance to the nonanalgesic effects often occurs. As our study shows, it is possible to use opioid substitution to find, in most patients (81%), a good balance between adverse side effects and good pain relief.
In conclusion, different chronic noncancer pain syndromes can be relieved by chronic opioid therapy. A patient cannot be declared as unresponsive to an opioid until a trial of different opioids has been tried. If it is necessary to change the opioid prescription because of intolerable side effects or ineffectiveness, with each new opioid tested, the number of patients to whom this new prescription will be effective increases. In addition, failure of one opioid cannot predict the patient’s response to another opioid.
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© 2000 International Anesthesia Research Society
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