Quang-Cantagrel, Nathalie Do MD; Wallace, Mark S. MD; Magnuson, Scott K. MD
Managing chronic noncancer pain in patients is a challenge to physicians who care for these individuals. As the use of opioids for the management of cancer and acute postoperative pain is well established, the long-term administration of opioids for patients with chronic noncancer pain remains controversial (1,2). This controversy results from confusion about pathologies which could benefit from opioids and misconceptions about addiction and tolerance that may result from long-term opioid administration. Some retrospective surveys have shown the efficacy of opioids in different pathologies (3,4), and randomized controlled studies have supported the efficacy of opioid treatment of patients with nonmalignant pain (5,6). These trials suggest that opioids can improve the level of analgesia and quality of life in some patients. The goal of pain treatment in outpatients with chronic pain is not only pain relief but also recovery of physical function, permitting an active social life and return to work. Therefore, the physician should try to find the balance between adverse side effects and the benefits of pain relief. To achieve this, a trial of multiple opioid therapies may be required before deciding if long-term opioid pain management is feasible. The goal of this retrospective analysis was to describe the concept of opioid substitution for identifying the best opioid for long-term therapy in chronic noncancer pain.
This retrospective chart review included 86 outpatients with chronic noncancer pain who were referred to the University of California San Diego, Pain Clinic. We included patients who started receiving one of four long-acting opioids administered on a time-contingent basis between 1994 and 1998. The first choice opioids included timed-release morphine, timed-release oxycodone, methadone, and transdermal fentanyl patch. All of these medications are μ-opioid agonists most frequently used in long-term management of chronic pain (1,4,6,7). Patient demographics included age, sex, and pain diagnosis. We tried to keep concurrent medications stable during the opioid titration. For each opioid tested, we noted the duration of the prescription, the efficacy, the side effects, and the doses administered. At each consultation, the patient evaluated the efficacy of treatment as inadequate if pain relief was <50% and adequate if pain relief was 50% or greater. The side effects were evaluated by having the patient give a score of 0–100, with 0 being no side effect and 100 being the worst imaginable side effect. If all side effect scores were <30, it was considered acceptable and tolerable. Any side effect score >30 was considered unacceptable. The starting opioid was chosen based on discussion with the attending physician and the patients. Factors that determined the starting opioid included allergies, cost, and patient preference for delivery route. After starting the opioid, the patients continued receiving this therapy for at least 1 wk. Dosing ranges for each of the opioids included: 1) timed-release morphine 15–60 mg three times per day, 2) timed-release oxycodone 10–80 mg three times per day, 3) methadone 5–20 mg four times per day, and 4) fentanyl patch 25–100 μg/hour. The dosage ranges were based on the clinic’s practice experience. Patients were allowed to increase the dose at weekly intervals if they had less than a 50% reduction in pain and a side effect score of <30 of 100. Dosage increases for each of the opioids used were as follows: 1) timed-release morphine 15 mg/dose, 2) timed-release oxycodone 20 mg/dose, 3) methadone 5 mg/dose, and 4) fentanyl patch 25-μg increments. If they could achieve a greater than 50% reduction in pain and a side effect score of <30 of 100, they were allowed to remain on the opioid therapy. Another opioid was chosen if one or more of the following occurred: 1) the maximum dose was reached without adequate pain relief, or 2) a side effect score was greater than 30 of 100. At this point, another opioid was chosen based on discussion with the attending physician and the patients and included timed-release morphine, timed-release oxycodone, methadone, transdermal fentanyl patch, levorphanol, oxycodone, and hydrocodone. Once the patient was stabilized on an opioid regimen, they either remained in the pain clinic for continuing management or were transferred to the primary care physician for management.
Statistical analysis of the data was performed by using the Kruskall-Wallis test and the Mann-Whitney U-test, if appropriate. Statistical significance was assumed where probabilities were <0.05.
The study included 86 patients, 50 women and 36 men with a median age of 42 yr (range 23–83). Patient diagnoses were back pain (31), neuropathy (20), joint pain (13), visceral pain (7), reflex sympathetic dystrophy (RSD) (7), headache (5), and fibromyalgia (3). The visceral pain was caused by chronic pancreatitis in three patients, was caused by endometriosis in three patients, and occurred after a gastrectomy in one patient. The mean length of follow-up in the pain clinic was 8.8 ± 6.3 mo (mean ± SD). The mean number of opioids tested by patients during the study was 2.3 ± 1.4.
The distribution of the drugs prescribed as first choice were timed-release morphine (33), timed-release oxycodone (18), methadone (29), and transdermal fentanyl (6). The doses and mean duration of prescription of the different opioids prescribed as the first choice are shown in Table 1. There was no statistical difference between effective doses and doses of drug stopped for ineffectiveness. Thirty-one patients received benefit from the first medication prescribed. The other 54 patients stopped the first prescription because of intolerable side effects in 25 cases (30%) and because of ineffectiveness in 29 cases (34%). One patient with rheumatoid arthritis stopped the opioid therapy when her joint pain was improved with the reintroduction of a previous medication, which had been temporarily stopped because of a kidney alteration. The most common intolerable side effects were nausea/vomiting (40%), sedation (32%), and itching (24%).The efficacy and the reasons of termination for the different first choice drugs prescribed are shown in Table 2. The first opioid prescribed was effective for 31 patients in whom the diagnosis was back pain (17), neuropathy (3), joint pain (3), visceral pain (3), headache (2), RSD (2), and fibromyalgia (1). There was no statistical correlation between diagnosis and opioid effectiveness in the first choice.
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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