Morphine versus methadone in the pain treatment of advanced-cancer patients followed up at home

PURPOSE: The aim of this study was to evaluate the analgesic and adverse effects and the doses of methadone in comparison to morphine. PATIENTS AND METHODS: A prospective randomized study was performed in a sample of 40 patients with advanced cancer who required strong opioids for their pain management. Patients were treated with sustained-release morphine or methadone in doses titrated against the effect administered two or three times daily according to clinical need. Opioid doses, adjuvant medications, symptoms associated with opioid therapy, pain intensity, and pain mechanisms were recorded. The opioid escalation indices in percentage (OEI%) and milligrams (OEImg) were calculated. The effective analgesic score (EAS) that monitors the analgesic consumption-pain ratio was also calculated at fixed weekly intervals. RESULTS: differences in pain intensity were found. Patients treated with methadone reported values of OEI significantly less than those observed in patients treated with morphine. Seven patients in the methadone group maintained the same initial dosage until death, whereas only one patient in the morphine group did not require opioid dose escalation. A more stable analgesia in time in patients treated with methadone was shown by the low number of gaps in EASs reported. Symptom frequencies and intensities were similar in the two groups. CONCLUSION: Methadone is a drug of indisputable value in the treatment of cancer pain, and an unbalanced focus on the risks of inappropriate use rather than the benefits should not compromise the use of a relevant alternative to morphine in the management of cancer pain.     

Visual function in neurofibromatosis

We performed an open-label pilot study to define analgesic efficacy, acceptability, and toxicity of transdermal fentanyl in an ambulatory population of patients with cancer pain. Our 7-day study included 35 patients, all of whom had failed a trial of an opioid analgesic conventionally used for moderate pain. Patients received either a 25 micrograms/hr or 50 micrograms/hr fentanyl transdermal patch depending on prior opioid dose. Pain was measured daily utilizing visual analogue (VAS) and categorical (CAT) scales. Hours of nighttime sleep, quality of life, toxicities, and use of rescue medication were also assessed. There was a 24%-29% reduction in mean VAS and CAT pain scores as compared with the baseline and a 25% increase in mean hours of nighttime sleep. Fifty-nine percent of those patients responding (46% of all study patients) were satisfied to very satisfied with the analgesia provided by transdermal fentanyl. Six percent of all study patients were not at all satisfied with the pain relief obtained. Toxicities were similar to those seen with other opioids. No patient developed severe sedation or respiratory depression. The 25-50 micrograms/hr patch appears to be a safe starting dosage in ambulatory patients previously receiving opioids conventionally used for moderate pain.     

Effects of Ca2+ channel blockers on Ca2+ loading induced by metabolic inhibition and hyperkalemia in cardiomyocytes

The treatment of neuropathic pain with opioid analgesics is a matter of controversy among clinicians and clinician scientists. Although neuropathic pain is usually believed to be only slightly responsive to opioids, several studies show that satisfactory analgesia can be obtained if adequate doses are administered. In the present study, we tested the effectiveness of buprenorphine in 21 patients soon after thoracic surgery (nociceptive postoperative pain) and 1 month after surgery in the same 21 patients who developed postthoracotomy neuropathic pain with a burning, electrical and shooting quality. According to a double-blind randomized study, the analgesic dose (AD) of buprenorphine needed to reduce the long-term neuropathic pain by 50% (AD50) was calculated and compared to the AD50 in the immediate postoperative period. We found that long-term neuropathic pain could be adequately reduced by buprenorphine. However, the AD50 in neuropathic pain was significantly higher relative to the AD50 in the short-term postoperative pain, indicating a lower responsiveness of neuropathic pain to opioids. We also found a strict relationship between the short-term and long-term AD50, characterized by a saturating effect. In fact, if the AD50 soon after surgery was low, the AD50 increase in the long-term neuropathic pain was threefold. By contrast, if the AD50 soon after surgery was high, the AD50 in neuropathic pain was only slightly increased. This suggests that, though neuropathic pain is indeed less sensitive to opioids, in some neuropathic patients a large amount of opioid resistance is already present in other painful conditions.     

Factors associated with refractory cancer pain

Cancer pain can be effectively controlled in most patients by classical pharmacological treatment. We retrospectively studied the characteristics and factors associated with non responsive pain. Between 1989 and 1996, 1767 patients were referred to our pain center; 831 (47%) had cancer pain and from 787 evaluable cases 118 (15%) experienced non-controlled pain whereas good pain control was achieved within a few days in 669 (85%) patients. Gender, age, cancer type, metastasis, initial pain intensity, nociceptive or neuropathic components and administration of adjuvant therapies were similar in both groups. On the other hand, diffuse pain, abdominal pain, terminal care, near death and doses of strong opioids were significantly different. Factors associated with therapeutic failure were conflicts, life and complications and breakthrough pain. In the presence of refractory cancer pain the factors predictive of therapeutic failure should be identified in order to optimize individual pain treatment.     

Efficacy of oxycodone in neuropathic pain: a randomized trial in postherpetic neuralgia

OBJECTIVE: Although opioid analgesics are used in the management of neuropathic pain syndromes, evidence of their efficacy remains to be established. We evaluated the clinical efficacy and safety of oxycodone in neuropathic pain using postherpetic neuralgia as a model. METHODS: Patients with postherpetic neuralgia of at least moderate intensity were randomized to controlled-release oxycodone 10 mg or placebo every 12 hours, each for 4 weeks, using a double-blind, crossover design. The dose was increased weekly up to a possible maximum of 30 mg every 12 hours. Pain intensity and pain relief were assessed daily, and steady (ongoing) pain, brief (paroxysmal) pain, skin pain (allodynia), and pain relief were recorded at weekly visits. Clinical effectiveness, disability, and treatment preference were also assessed. RESULTS: Fifty patients were enrolled and 38 completed the study (16 men, 22 women, age 70+/-11 years, onset of postherpetic neuralgia 31+/-29 months, duration of pain 18+/-5 hours per day). The oxycodone dose during the final week was 45+/-17 mg per day. Compared with placebo, oxycodone resulted in pain relief (2.9+/-1.2 versus 1.8+/-1.1, p=0.0001) and reductions in steady pain (34+/-26 versus 55+/-27 mm, p=0.0001), allodynia (32+/-26 versus 50+/-30 mm, p=0.0004), and paroxysmal spontaneous pain (22+/-24 versus 42+/-32 mm, p=0.0001). Global effectiveness, disability, and masked patient preference all showed superior scores with oxycodone relative to placebo (1.8+/-1.1 versus 0.7+/-1.0, p=0.0001; 0.3+/-0.8 versus 0.7+/-1.0, p=0.041; 67% versus 11%, p=0.001, respectively). CONCLUSIONS: Controlled-release oxycodone is an effective analgesic for the management of steady pain, paroxysmal spontaneous pain, and allodynia, which frequently characterize postherpetic neuralgia.     

Poor leadership behind poor pain relief. Medical audit of cancer-related pain treatment

A clinical audit of the treatment of cancer-related pain, ordered by Stockholm County Council and the Karolinska Institute, was performed at two Stockholm hospitals. Of 153 consecutive cancer patients interviewed while attending the preoperative out-patient clinic of the Dept. of Anaesthesiology at Karolinska Hospital, 93 (61%) reported pain varying in intensity from 2.4 to 6.6 on a 10-point visual analogue scale. The pain was cancer-related in 20 patients, treatment-related in 28 patients, and associated with disease in 40 patients (e.g., post-herpetic neuralgia, urethritis, decubital ulcer or constipation). Nine patients had undetected neuropathic pain components, and 18 patients reported both significant pain intensity and dissatisfaction with the treatment. The auditors found these patients to have persistent pain problems despite the availability of time and opportunity to resolve them. The audit included interviews with staff at three hospital departments, who filled in questionnaires, and scrutiny of the medical records of about 120 cancer patients, 5-10 records from each department being selected to illustrate the management of pain problems. Findings from the staff questionnaires and interviews were compared with the picture of pain management elicited from the patients' records. The hospital departments were all found to be characterised by similar problems: lack of pain analysis or diagnosis, failure to detect neuropathic pain components, and underdosing of opioid analgesics irrespective of pain intensity. The auditors' conclusions included a need of pain education, particularly for doctors as fewer doctors than nurses had attended pain courses.     

Does intrathecal morphine in the treatment of cancer pain induce the development of tolerance?

OBJECTIVE: This retrospective study was designed to investigate whether chronic lumbar intrathecal administration of morphine leads to the development of opioid tolerance in patients suffering from intractable cancer pain. METHODS: Between 1978 and 1995, 159 patients with refractory cancer pain were treated with intrathecal morphine in our Multidisciplinary Pain Center. The treatment consisted of preservative-free morphine administered through an access port as a single bolus. In this series of patients (n = 159), the daily doses of intrathecal morphine were determined as a function of duration of follow-up. RESULTS: The mean follow-up period was 95 days (range, 5-909 d), the mean starting daily dose of intrathecal morphine was 2.69 mg (range, 1-7.5 mg), and the mean terminal dose was 7.82 mg (range, 1-80 mg). The results demonstrated that only a moderate increase in daily dose of intrathecal morphine was required during the course of treatment (a two- to threefold increase for a 3-mo period). Furthermore, the dose increment was similar for patients followed up for more or less than 60 days. This increase did not result in any central opioid-related side effects, and the pain was managed satisfactorily. CONCLUSION: The requirement for a moderate increase in intrathecal opioid doses reflects the development of tolerance but did not limit the patients' ability to obtain adequate analgesia during the course of their painful disease.     

Propentofylline inhibits production of TNFalpha and infection of LP-BM5 murine leukemia virus in glial cells

Much evidence points to the involvement of N-methyl-D-aspartate (NMDA) receptors in the development and maintainance of neuropathic pain. In neuropathic pain, there is generally involved a presumed opioid-insensitive component, which apparently can be blocked by NMDA receptor antagonists. However, in order to obtain complete analgesia, a combination of an NMDA receptor antagonist and an opioid receptor agonist is needed. Recent in vitro data have demonstrated that methadone, ketobemidone, and dextropropoxyphene, in addition to being opioid receptor agonists, also are weak noncompetitive NMDA receptor antagonists. Clinical anecdotes suggest that the NMDA receptor antagonism of these opioids may play a significant role in the pharmacological action of these compounds; however, no clinical studies have been conducted to support this issue. In the present commentary, we discuss evidence for the NMDA receptor antagonism of these compounds and its relevance for clinical pain treatment; an overview of structure-activity relationships for the relevant opioids as noncompetitive NMDA receptor antagonists also is given. It is concluded that although the finding that some opioids are weak noncompetitive NMDA receptor antagonists in vitro has created much attention among clinicians, no clinical studies have been conducted to evaluate the applicability of these compounds in the treatment of neuropathic pain conditions.     

A prospective study of long-term intrathecal morphine in the management of chronic nonmalignant pain

OBJECTIVE: To examine in a prospective manner the long-term safety and efficacy of chronic intrathecal morphine in patients with severe, nonmalignant pain refractory to less invasive modalities. METHODS: Forty patients with severe, chronic nonmalignant pain poorly managed by systemic medications were identified as candidates for intraspinal trial of morphine. Thirty participants reported successful pain relief during trial and were implanted with an intraspinal delivery system. Standardized measures of pain and functional status were assessed before treatment was begun and at defined intervals during the subsequent 24 months. Intrathecal opioid use and pharmacological and device-related complications were also monitored. RESULTS: The participants had a mean age of 58 +/- 13 years and a mean pain duration of 8 +/- 9 years. Fifty-three percent of the study participants were women. Pain type was characterized as mixed neuropathic-nociceptive (15 of 30 patients, 50%), peripheral neuropathic (10 of 30 patients, 33%), deafferentation (4 of 30 patients, 13%), or nociceptive (1 of 30 patients, 3%). Forty-seven percent of the patients were diagnosed with failed back surgery syndrome. Significant improvement over baseline levels of visual analog scale pain was measured at each follow-up examination after implant. Overall, 50% (11 of 22 patients) of the population reported at least a 25% reduction in visual analog scale pain after 24 months of treatment. In addition, the McGill Pain Questionnaire, visual analog scale measures of functional improvement and pain coping, and several subscales of the Chronic Illness Problem Inventory showed improvement throughout the follow-up period. Pharmacological side effects were managed medically by morphine dose reduction, addition of bupivacaine, or replacement of morphine with hydromorphone. Device-related complications requiring repeat operations were experienced by 20% of the patients. CONCLUSION: Continuous intrathecal morphine can be a safe, effective therapy for the management of severe, nonmalignant pain among a carefully selected patient population and can result in long-term improvement in several areas of daily function.     

Comparison of pain control medication in three age groups of elderly patients

There are no published reports of burn pain management in the elderly population. To assess the range of requirement and use of opioids among elderly patients with burns of different age categories, a retrospective review of 89 consecutive admissions of patients over 55 years of age (January 1995 through July 1996) was conducted. Complete data were available on 44 patients with a burn mean total body surface area of 17.2%. Patient ages ranged from 55 to 92 years. Individuals were divided into three age categories: Group I (55 to 65) n = 20; Group II (66 to 75) n = 14; and Group III (76 to 92) n = 10. Use of commonly prescribed opioids for procedural pain and breakthrough pain were evaluated. We compared the opioid equivalents of medications prescribed versus the actual amount administered. Paired t tests comparing minimum amount of medication ordered with that given revealed Group I patients received significantly more procedural medication than the minimum prescribed (t = 3.88, p = 0.001), and that Group III patients were given significantly less as needed medication than the minimum prescribed (t = 2.58, p < 0.05).     

Clinical efficacy and safety of a novel controlled-release morphine suppository and subcutaneous morphine in cancer pain: a randomized evaluation

PURPOSE: A significant number of cancer patients will require an alternate route of morphine administration at some point during their illness. This study compared the clinical efficacy and safety of a novel morphine sulfate controlled-release suppository (MS-CRS) and subcutaneous (SC) morphine in patients with cancer pain. METHODS: Thirty patients with cancer pain were randomized in a double-blind crossover study to MS-CRS every 12 hours or SC morphine every 4 hours for 4 days each, using a 2.5:1 analgesic equivalence ratio. Pain intensity was assessed using a visual analog scale (VAS) and the Present Pain Intensity Index of the McGill Pain Questionnaire. Nausea and sedation were also assessed with a VAS. Evaluations were made by the patient at 8 AM, noon, 4 PM, and 8 PM and rescue morphine consumption recorded. RESULTS: Twenty-three patients completed the study (13 men and 10 women; mean age, 64.0 +/- 2.0 years) and were treated with mean daily MS-CRS and SC morphine doses of 326 +/- 69 mg and 138 +/- 28 mg, respectively. There was a small but significant difference in overall ordinal pain-intensity scores in favor of MS-CRS (0.7 +/- 0.1 v 0.9 +/- 0.1, P = .0459). There were no significant differences between MS-CRS and SC morphine in overall VAS scores for pain intensity (13 +/- 3 v 13 +/- 3 mm), sedation (23 +/- 3 v 25 +/- 4 mm), and nausea (8 +/- 2 v 9 +/- 2 mm). The mean daily rescue analgesic consumption during MS-CRS and SC morphine did not differ significantly (1.2 +/- 0.4 v 1.2 +/- 0.4 doses/d). CONCLUSION: MS-CRS, administered every 12 hours, provides analgesia comparable to SC morphine and represents a reliable, noninvasive alternative method of pain control for patients unable to take oral morphine.     

An office approach to the diagnosis of chronic cough

BACKGROUND: Some cancer patients require invasive techniques for control of chronic cancer pain. Many patients have benefited from local administration of opioids and anesthetics through an epidural catheter. However, epidural abscess and meningitis are side effects of epidural catheters that have serious morbidity and mortality. METHODS: In a retrospective study, the charts of all patients who received an epidural catheter for the management of chronic cancer pain in a 3-year period (1993-1996) were reviewed. Patients with nervous system infections were identified and pertinent clinical, radiologic (magnetic resonance imaging), and bacteriologic data were analyzed. RESULTS: Ninety-one patients received 137 epidural catheters for a total of 4326 catheter days. All but four patients had died at the time of the final analysis. The median survival after placement of the first epidural catheter was 38 days (range, 1 day--> 1000 days). Seventy-two patients received a percutaneous port whereas 19 patients were treated with an implanted subcutaneous port. Adequate pain relief was obtained in 76% of the 58 patients with nociceptive pain and in 73% of 33 patients with neuropathic pain. All neuropathic pain was associated with active tumor and could be classified as nociceptive nerve pain. Technical complications and superficial infections occurred in as many as 43% of patients. Deep infections occurred in 12 patients, 11 of whom had a spinal epidural abscess. CONCLUSIONS: Deep infection is a frequent complication of epidural analgesia and is associated with a high morbidity and mortality. Only cancer patients with a short life expectancy (< or =3 months) should be treated with epidural analgesia.     

Opioid therapy for chronic noncancer back pain. A randomized prospective study

STUDY DESIGN: A randomized, open, long-term, repeated-dose comparison of an anti-inflammatory drug and two opioid regimens in 36 patients with back pain. OBJECTIVES: To examine the long-term safety and efficacy of chronic opioid therapy in a randomized trial of patients with back pain. METHODS: All participants underwent a 4-week washout period of no opioid medication before being randomly assigned to one of three treatment regimens for 16 weeks: 1) naproxen only, 2) set-dose oxycodone, or 3) titrated-dose oxycodone and sustained-release morphine sulfate. All patients then were assigned to a titrated dose of opioids for 16 weeks and then gradually tapered off their medication for 12 weeks. Finally, all participants were monitored for a 1-month posttreatment washout period. Each patient was called once a week for a report on pain, activity, mood, medication, hours awake, and adverse effects and was monitored carefully for signs of abuse and noncompliance. RESULTS: Weekly reports during the experimental phase showed the titrated-dose group to have less pain (P < 0.001) and less emotional distress (P < 0.001) than the other two groups. Both opioid groups were significantly different from the naproxen-only group. During the titration phase, patients also reported significantly less pain and improved mood. Few differences were found in activity or hours asleep, or between average pretreatment and posttreatment phone-interview and questionnaire variables. No adverse events occurred, and only one participant showed signs of abuse behavior. CONCLUSIONS: The results suggest that opioid therapy has a positive effect on pain and mood but little effect on activity and sleep. Opioid therapy for chronic back pain was used without significant risk of abuse. However, tapered-off opioid treatment is palliative and without long-term benefit.     

Radiation therapy in the management of symptomatic bone metastases: the effect of total dose and histology on pain relief and response duration

PURPOSE: In order to better define variables and factors that may influence the pain response to radiation, and to look for a radiation regimen that can assure the highest percentage and the longest duration of pain relief, we performed a prospective, although not randomized, study on patients with bone metastases from various primary sites. METHODS AND MATERIALS: From December 1988 to March 1994, 205 patients with a total of 255 solitary or multiple bone metastases from several primary tumors were treated in our radiotherapy center with palliative intent. Irradiation fields were treated with three main fractionation schedules: (1) Conventional fractionation: 40-46 Gy/20-23 fractions in 5-5.5 weeks; (2) Short course: 30-36 Gy/10-12 fractions in 2-2.3 weeks; (3) Fast course: 8-28 Gy/1-4 consecutive fractions. Pain intensity was self-assessed by patients using a visual analogic scale graduated from 0 (no pain) to 10 (the strongest pain one can experience). Analgesic requirement was assessed by using a five-point scale, scoring both analgesic strength and frequency (0 = no drug or occasional nonopioids; 1 = Nonopioids once daily; 2 = Nonopioids more than once daily; 3 = Mild opioids (oral codeine, pentazocine, etc.), once daily; 4 = Mild opioids more than once daily; 5 = Strong opioids (morphine, meperidine, etc.). Complete pain relief meant the achievement of a score < or = 2 in the pain scale or 0 in the analgesic requirement scale. Partial pain relief indicated a score of 3 to 4 or of 1 to 2 on the former and latter scale, respectively. RESULTS: Total pain relief (complete + partial) was observed in 195 (76%) sites, in 158 of which (62%) a complete response was obtained. Metastases from NSC lung tumors appeared to be the least responsive among all primary tumors, with 46% complete pain relief in comparison to 65% and 83% complete relief in breast (p = 0.04) and in prostate metastases (p = 0.002), respectively. A significant difference in pain relief was detected among the several ranges of total dose delivered to the painful metastases, with 81%, 65%, and 46% complete relief rates in the 40-46 Gy, 30-36 Gy (p = 0.03), and 8-28 Gy (p = 0.0001) dose ranges respectively. A straight correlation between total dose and complete pain relief was confirmed by the curve calculated by the logistic model which shows that doses of 30 Gy or more are necessary to achieve complete pain relief in 70% or more of bone metastases. This correlation holds also for the duration of pain control, as shown by the actuarial analysis of time to pain progression. Multivariate analyses, with complete pain relief and time to pain progression as endpoints show a highly significant effect of radiation dose (p = 0.0007) and performance status (p = 0.003), with lower rates of complete pain relief and shorter time to pain progression observed after smaller radiation total doses or higher Eastern Cooperative Oncology Group (ECOG) scores. CONCLUSION: Although single-dose or short course irradiation is an attractive treatment in reducing the number of multiple visits to radiotherapy departments for patients with painful bone metastases, it is nevertheless clear that aggressive protracted treatments seem to offer significant advantages especially for patients in whom the expected life span is not short.     

Government regulatory influences on opioid prescribing and their impact on the treatment of pain of nonmalignant origin

Interpretation of regulations establishing standards for prescribing opioids by government regulatory boards and drug-enforcement agencies is more restrictive for treatment of nonmalignant pain than for malignant pain. Authority to regulate opioids is provided by health practice acts enacted by state governments, and controlled substances acts, enacted by both state and federal governments. The methods used by boards/agencies to determine standards of practice for opioid use result in interpreting the language in these regulations based on myths, prejudices, and misinformation about opioids, and the unexamined belief that mere exposure of patients to these drugs causes psychological dependence (addiction) on them to all patients in all instances. Interpretation is also strongly influenced by a failure of regulatory and enforcement bodies to recognize their coequal obligation of making opioids readily available to those who need them for legitimate medical purposes, while simultaneously policing their diversion to illegitimate uses. Emphasis on the police function of preventing diversion is paramount. Disciplining practitioners using standards based on myths, prejudices, etc., reinforces physicians' fears of prescribing opioids for nonmalignant pain. Patients with nonmalignant pain who are not relieved if opioids are not provided will continue to suffer until regulatory boards/drug enforcement agencies define the standards of practice for opioid use for nonmalignant pain in clear and unequivocal terms. It is unlikely these standards will be developed until there is a consensus among pain specialists about opioid use for nonmalignant pain because boards/agencies have no consistent, reliable source of expert information. Pain specialists should initiate efforts to develop this consensus.     

The impact of postoperative pain on the development of postoperative delirium

We performed a prospective observational study to examine the role of postoperative pain and its treatment on the development of postoperative delirium. Pain was measured in direct patient interviews using a visual analog scale (VAS) and was assessed for pain at rest, pain with movement, and maximal pain over the previous 24 h. Postoperative delirium was diagnosed during these interviews by using the confusion assessment method (CAM) and/or by using data from the medical record and the hospital's nursing intensity index. The method of postoperative analgesia, type of opioid, and cumulative opioid dose were also recorded. After controlling for known preoperative risk factors for delirium (age, alcohol abuse, cognitive function, physical function, serum chemistries, and type of surgery), higher pain scores at rest was associated with an increased risk of delirium over the first 3 postoperative days (adjusted risk ratio 1.20, P = 0.04). Pain with movement and maximal pain were not associated with delirium. Method of postoperative analgesia, type of opioid, and cumulative opioid dose were not associated with an increased risk of delirium. We conclude that more effective control of postoperative pain reduces the incidence of postoperative delirium. Implications: We performed daily interviews in a large population of patients undergoing noncardiac surgery to measure their level of pain and development of delirium. We found an association between higher pain levels at rest and the development of delirium. Our results suggest that better control of postoperative pain may reduce this serious complication.     

The effects of digitalis-like compounds on rat lenses

We examined the effects of several opioids that vary in intrinsic efficacy at the mu-opioid receptor alone and in combination with morphine in a rat warm water tail withdrawal procedure using 50 degrees C and 52 degrees C water (i.e., low- and high-stimulus intensities). Morphine, levorphanol, dezocine, and buprenorphine produced dose-dependent increases in antinociception using both stimulus intensities. Butorphanol produced maximal levels of antinociception at the low, but not at the high, stimulus intensity, whereas nalbuphine failed to produce antinociception at either stimulus intensity. For cases in which butorphanol and nalbuphine failed to produce antinociception alone, these opioids dose-dependently antagonized the effects of morphine. When levorphanol, dezocine, and buprenorphine were combined with morphine, there was a dose-dependent enhancement of morphine's effects. Similar effects were obtained at the low-stimulus intensity when butorphanol was administered with morphine. In most cases, the effects of these combinations could be predicted by summating the effects of the drugs when administered alone. These results indicate that the level of antinociception produced by an opioid is dependent on the intrinsic efficacy of the drug and the stimulus intensity. Furthermore, the level of antinociception produced by the opioid, not necessarily the opioids' intrinsic efficacy, determines the type of interaction among opioids. Implications: Compared with high-efficacy opioids, lower efficacy opioids produce lower levels of pain relief, especially in situations of moderate to severe pain. When opioids are given in combination, the effects can only be predicted on the basis of the antinociception obtained when the drugs are administered alone.