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The effect of ketamine on opioid-induced acute tolerance: can it explain reduction of opioid consumption with ketamine-opioid analgesic combinations?

UNLABELLED: Ketamine administered intraoperatively in very small doses reduces postoperative opioid consumption. We suggest that this effect is the result of attenuation of acute tolerance to the analgesic effect of opioids. We sought to demonstrate that acute tolerance induced by alfentanil infusion can be attenuated by a dose of ketamine that is too small to produce a direct antinociceptive effect. The experiments were conducted in rats with the use of an infusion algorithm designed to maintain a constant plasma level of the opioid for 4 h. The degree of acute tolerance was determined on the basis of decline in the level of analgesia measured with a tail compression test. Ketamine (10 mg/kg) did not change the baseline pain threshold and did not increase the peak of alfentanil-induced analgesia. At the same time, it attenuated the development of acute tolerance to analgesia during alfentanil infusion and suppressed rebound hyperalgesia observed the day after the infusion. These effects were similar to those observed with dizocilpine (0.1 mg/kg). The development of acute tolerance to analgesia induced by the infusion of an opioid can be attenuated by ketamine administered in doses that are not large enough to provide a direct antinociceptive effect. Therefore, ketamine has the potential to reduce opioid consumption even in subanalgesic doses. IMPLICATIONS: Ketamine attenuated the development of acute tolerance to analgesia during alfentanil infusion and suppressed rebound hyperalgesia observed the day after the infusion.

Alfentanil↗

The effect of mandibular nerve block on opioid consumption, nausea and vomiting in bilateral mandibular osteotomies.

UNLABELLED: The purpose of this study was to compare the efficacy of a mandibular nerve block to placebo, in patients undergoing mandibular osteotomy surgery, regarding opioid consumption and adverse opioid induced side effects. Forty healthy individuals with a mean age of 19.7 years participated in the study. All subjects received lidocaïn 2% + adrenaline 1/80,000 versus placebo for mandibular nerve block in a randomized double-blind manner. Opioid consumption and opioid related side effect such as postoperative nausea and vomiting (PONV), and respiratory depression were assessed. RESULTS: The placebo group received significantly more sufentanil during the surgical procedure than the lidocaïngroup. There were no significant differences in adverse opioid induced side effects. In the postoperative phase there was no difference in additional pain intervention between the two groups. CONCLUSION: The mandibular block during mandibular osteotomy reduces intra-operative opioid consumption but does not alternate the opioid related side-effects in the postoperative phase.

Adult↗

International opioid consumption.

The aim of the present study was to analyse the opioid consumption in the 10 most opioid-consuming countries in relation to the Danish consumption. The results revealed, that the total opioid consumption has increased in all of the 10 most opioid consuming countries (range 26-1423%). In Denmark, the total opioid consumption increased 353% from 1981 to 1993, exceeding 1.45 million defined daily doses per 1 million inhabitants in 1993, which is the highest in the world. Of these, morphine accounted for 39%, methadone 22%, ketobemidone 21% and buprenorphine 14%. The consumption of long-acting opioids (morphine sustained release, methadone, buprenorphine) and short acting opioids (others) increased 1427% and 105%, respectively. Analysis of a sample of 1854 prescriptions made by general practitioners for opioids revealed, that less than 10% of the prescriptions were issued for cancer pain conditions. In conclusion of other countries consider Denmark as worthy of imitation concerning opioid treatment in cancer pain, attention should be paid to the pattern of the Danish opioid consumption, which is outstanding with respect to quantity.

Analgesics, Opioid↗

[Analgesia in colon surgery. Can the use of NSAIDs reduce the opioid consumption following conventional and laparoscopic interventions?].

BACKGROUND: The goal of our study was to evaluate the morphine-sparing effect of nonsteroidal anti-inflammatory drugs (NSAIDs) following both conventional and laparoscopic colon surgery. MATERIALS AND METHODS: In this prospective, randomized clinical trial, 180 patients were assigned to three groups. Two groups received either paracetamol or parecoxib/valdecoxib in addition to piritramid via patient-controlled or nurse-controlled analgesia pump. Patients in the control group received piritramid only. The total piritramid consumption during hospital stay was recorded. RESULTS: Total opioid consumption was significantly lower in the two groups who received NSAIDs. Comparing conventional and laparoscopic surgery, the latter group had much lower opioid consumption. CONCLUSION: The use of NSAIDs following colon surgery significantly reduces postoperative opioid consumption.

Acetaminophen↗

Legal opioid consumption in Denmark 1981-1993.

According to the World Health Organisation, a country's morphine consumption is an important indicator of progress in cancer pain relief. Due to its very high opioid consumption, Denmark is often pointed out as a country worthy of imitation. The aim of the present study was to analyse Danish opioid consumption in order to elucidate the usage pattern and to identify the consumers. Total opioid consumption increased 353% from 1981 to 1993, exceeding 1.45 million defined daily doses per million inhabitants in 1993. Morphine accounted for 39%, methadone 22%, ketobemidone 21% and buprenorphine for 14% of the consumption use. The consumption of long acting opioids (sustained release morphine, methadone, buprenorphine) and short acting opioids (others) increased by 1427% and 105%, respectively. Analysis of a sample of 1854 prescriptions for opioids revealed that less than 10% of the prescriptions were issued for cancer pain conditions. It is concluded: that if other countries consider Denmark as worthy of imitation in opioid treatment for cancer pain, attention should be paid to the pattern of the Danish opioid consumption, which is outstanding with respect to quantity but the quality may be questionable.

Analgesia↗

Differences in postoperative opioid consumption in patients prescribed patient-controlled analgesia versus intramuscular injection.

The purpose of this study was to examine differences in opioid consumption in patients prescribed patient-controlled analgesia (PCA) versus intramuscular injection (IMI) in the early postoperative period after open abdominal surgery. A retrospective audit of 115 patients elicited demographic and clinical data. No significant differences were found between the demographic variables of the PCA and IMI groups. There was a significant difference in the mean opioid dose used during the first 3 postoperative days (p < .01). Mean opioid consumption was 136.89 mg for the PCA group and 50.79 mg for the IMI group. Although there was a reduction in the amount of opioid consumed over the first 3 postoperative days, the PCA group consistently consumed more opioid analgesia compared with the IMI group. Furthermore, there was a disproportionate reduction in opioid consumption between the two groups from Day 1 (r = .34; p < .01) to Day 3 (r = .14; p = .14). This study shows that the amount of analgesia consumed during the postoperative period by patients who had abdominal surgery varied markedly depending on the mode of analgesia (PCA or IMI). The difference in analgesic consumption was also found to increase throughout the 3-day postoperative period. This divergence in the amount of opioid consumption between patients who were prescribed PCA and patients who were prescribed IM analgesia heightens the need for vigilance in assessment and management of pain during the early postoperative period, particularly in patients prescribed IM analgesia on an "as-needed" basis.

Adult↗

Opioid consumption in hospitals of the Friuli-Venezia Giulia region: a four-year retrospective study.

AIMS AND BACKGROUND: Opioid consumption for analgesic purposes is considered an important indicator of the quality of cancer pain treatment. Italy's consumption ranks among the lowest in economically developed countries. A lack of systematic education of health care professionals regarding pain control and a sort of "opiophobia" induced by measures designed to control the improper use of drugs have been indicated as possible reasons for this trend. The aim of this study was firstly to evaluate the level of opioid consumption at inpatient institutions (where opioid prescription rules have never been subjected to any restriction) and secondly to survey the attitude of the physicians working in general hospitals and specialized oncology institutions (oncology centers and hospices) towards opioid administration. METHODS: The authors performed a four-year survey (1996-1999) on the consumption of major opioids (morphine, meperidine, buprenorphine, transdermal fentanyl) among all the inpatient institutions (six regional/provincial hospitals, eleven district hospitals, the Aviano Oncology Institute and two hospices) of the Friuli-Venezia Giulia region in North-Eastern Italy. To facilitate data interpretation, all the opioids were converted to milligrams equivalent of oral morphine (mg OME). Data on the number of days of hospitalization of oncological patients in every institution were also collected. RESULTS: The overall consumption of opioids was 9,299,177 mg OME (83.3%) and 1,845,060 mg OME (16.7%) in general hospitals and specialized oncology institutions, respectively. Overall, the number of days of hospitalization of oncological patients was 1,121,142 (87%) and 167,665 (13%) in general hospitals and specialized oncology institutions, respectively. The ratio between the total dosage of mg OME administered and the total number of hospitalization days in general hospitals and specialized oncology institutions was 8.29 mg OME/day and 11 mg OME/day, respectively. CONCLUSIONS: Our data show that in specialized oncology institutions, opioid consumption was proportionally higher than in general hospitals. This result indicates the attitude of the physicians of these institutions towards opioid administration, probably due to the training received on cancer pain treatment, and emphasizes the need to educate all health care workers involved in the management of cancer patients.

Analgesics, Opioid↗

Opioid consumption in Spain--the significance of a regulatory measure.

OBJECTIVE: To investigate the impact of new regulatory measures on opioid consumption in Spain during the period 1985-1998. METHODS: A search in the ECOM (Especialidades Consumo de Medicamentos) database of the Ministry of Health was made for the 1985-1998 period. This database contains information about drug preparations prescribed in primary care in the National Health System in Spain. RESULTS: Since 1985-1998, the overall opioid consumption has increased tenfold, from 94.7 DDD (defined daily dose) per million inhabitants per day to more than 1000 DDD. For the five drugs that require a special prescription form (morphine, methadone, pethidine, tilidine and fentanyl), the consumption has increased 13.5-fold. CONCLUSION: A huge increase in opioid consumption has occurred. In this increase, changes in supply and, to a lesser extent, regulatory measures have played an important role.

Analgesics, Opioid↗

Effects of adolescent nicotine exposure on opioid consumption and neuroendocrine responses in adult male and female rats.

Effects of adolescent nicotine exposure on illicit drug consumption and neuroendocrine functioning were examined in adult rats. Nicotine (NIC; 2 doses) or saline (SAL) was administered via osmotic minipumps to 30 male and 30 female adolescent Wistar rats for 19 days. After NIC/SAL cessation, oral opioid consumption was assessed in the home cage for 4 weeks. Plasma corticosterone and ACTH were measured at the end of the experiment. Low-NIC male rats consumed more fentanyl than did high-NIC male rats; opioid consumption among adult female rats was not altered by NIC exposure. Females consumed more fentanyl than did males, regardless of NIC history. NIC exposure increased adult corticosterone and ACTH levels in a dose-dependent manner. Results suggest important effects of adolescent NIC exposure, including altered neuroendocrine status and opioid consumption.

Adrenocorticotropic Hormone↗

Acute pain management in patients with prior opioid consumption: a case-controlled retrospective review.

The patient with a history of current opioid consumption presenting in the acute postoperative setting presents a challenge for pain management. Standard treatment dosages and strategies are often ineffective in providing pain relief. This retrospective case-control study reviews 4 years' experience of the Acute Pain Service (APS) at our institution providing care for 202 chronic pain and opioid-consuming (CPOC) patients, 6.6% of 3058 patients undergoing urologic, gynecologic, orthopedic and general surgical procedures. Controls matched for age, gender, date and type of surgery, and postoperative pain relief modality were found for 180 (89%) of these patients. Patients were provided patient-controlled analgesia (PCA), or epidural opioid analgesia (EOA with boluses of preservative-free morphine or bupivacaine (1:16% + 2 micrograms/ml fentanyl (B/F)). Records were reviewed for patient demographics, diagnoses, surgical procedures, pre-operative opioid use, days-on-service, analgesic requirement, pain scores and incidence of moderate/severe side effects. Patient demographics were similar between CPOC and control groups. When considering PCA alone, mean 24-h usage in controls was 42.8 (32.0) mg morphine (MS) equivalents differing significantly from CPOC patients' use of 135.8 (68.5) mg MS equivalents (P = 0.0001). EOA and B/F case studies showed similar results. Moderate sedation was experienced by 50% of CPOC patients receiving PCA. Differences in opioid usage, side effects, pain scores, sedation and prescribed treatment with anxiolytics were shown between CPOC patients and matched controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Disease↗

Personal past experience with opioid consumption affects attitudes and knowledge related to pain management.

The personal past experience with opioid consumption by hospital health care providers was examined for its influence on their attitudes toward and knowledge of pain management. Data were collected through a questionnaire that elicited demographic information, attitudes toward pain management, barriers to pain relief, and self-assessment of pain management knowledge. The sample ( N = 163) was divided into two groups according to past experience with opioids: 52% of participants had used opioids (UO) for pain relief in the past, and the rest had never done so (NO). UO participants noted that pain control treatment was not sufficient for pain relief, in contrast to NO participants ( p = .013). Pain management was considered a low priority relative to overall treatment by the UO group compared with the NO group ( p = .016). The former group also attributed major responsibility for inappropriate pain relief to the clinical staff (12% of the UO group vs. 1.4% of the NO group; p = .048) rather than to the patients (22.9% of the UO group vs. 32.9% of the NO group; p = .019). UO participants felt extremely competent in their ability to manage several aspects of pain therapy ( p < .05). These aspects included assessing cause of the pain (42.9% of the UO group vs. 29.3% of the NO group), selecting a starting dose for opioid therapy (26.9% of the UO group vs. 13.3% of the NO group), and using opioids intravenously (20.5% of the UO group vs. 8.3% of the NO group). Personal past experience regarding analgesic use is an important factor in evaluating attitudes toward pain and achieving optimal pain management outcomes.

Adult↗

Circadian distribution of oral opioid consumption in cancer patients.

Diurnal variations are reported in pain perception, potency of placebo and in the pharmacokinetics of morphine. It is not established if such diurnal variation should be reflected in the routine prescription of analgesic drugs to cancer patients. One approach for investigating this question is to study the circadian rhythm of patients' requests for analgesics. We included 40 patients with malignant disease and intolerable pain despite treatment with weak opioids. Weak opioids were stopped and the patients' pain treatment was restricted for the next 2 days to strong oral opioids (ketobemidone) given on an as-needed basis. The number and times of all ketobemidone administrations were recorded. No significant diurnal variation in use of ketobemidone was observed. A descriptive curve that interpolates between successive observations displayed only slight circadian fluctuations of opioid consumption. Thus, the data reported in this paper does not support the necessity of considering chronopharmacological factors in the routine prescription of oral opioids.

Adult↗

Intraoperative remifentanil infusion does not increase postoperative opioid consumption compared with 70% nitrous oxide.

BACKGROUND: Remifentanil is commonly used to replace nitrous oxide in general anesthesia to avoid the side effects of the latter. However, there are reports that intraoperative remifentanil infusion can lead to acute opioid tolerance. In this study, the authors tried to determine the dose of remifentanil comparable in efficacy to 70% nitrous oxide and to evaluate its effect on postoperative pain and morphine consumption after colorectal surgery using isoflurane anesthesia. METHODS: Sixty adult patients undergoing open colorectal surgery were randomly assigned to receive either remifentanil or 70% nitrous oxide along with isoflurane anesthesia. After morphine analgesia titration in the postanesthesia care unit, patient-controlled analgesia was commenced. Morphine consumption and pain were scored at rest and during cough or movement for 24 h. RESULTS: The mean remifentanil infusion rate was 0.17 mug . kg . min. The median visual analog pain score on arrival in the postanesthesia care unit was 1 (0-10) in the nitrous oxide group and 3 (0-9) in the remifentanil group (P < 0.05). Otherwise, there was no difference in pain scores at 5, 10, and 15 min and no difference in the total morphine consumption during the stay in the postanesthesia care unit. The two groups had similar total morphine consumption in the first 24 h and pain scores at rest and during movement. The incidence of postoperative nausea and vomiting was 10% in both groups. There was no difference in the sedation scores. CONCLUSION: The substitution of 70% nitrous oxide with remifentanil at a mean infusion rate of 0.17 mug . kg . minute for colorectal surgery did not affect postoperative opioid consumption.

Adult↗

S(+)-ketamine as an analgesic adjunct reduces opioid consumption after cardiac surgery.

There are no studies evaluating S(+)-ketamine for pain management after sternotomy. In this prospective, randomized, double-blind, placebo-controlled clinical trial, we evaluated the efficacy and feasibility of S(+)-ketamine as an adjunctive analgesic after cardiac surgery. Ninety patients scheduled for elective coronary artery bypass grafting (CABG) were randomized to receive either a 75 microg/kg bolus of S(+)-ketamine followed by a continuous infusion of 1.25 microg . kg(-1) . min(-1) for 48 h (n = 44) or placebo (normal saline bolus and infusion) (n = 46). From the time of tracheal extubation, patients could access an opioid (oxycodone) via a patient-controlled analgesia device, and the cumulative oxycodone doses were measured over 48 h. Pain was evaluated on a visual analog scale three times daily. The quality of recovery, patient satisfaction with pain management, and adverse effects were recorded. The cumulative oxycodone consumption during the first 48 postoperative hours was less in the S(+)-ketamine group (103 +/- 44 mg) than in the placebo group (125 +/- 45 mg; mean difference, 22 mg; 95% confidence interval for the difference, 3-40 mg; P = 0.023). Pain scores did not differ between the groups at rest (P = 0.17) or during a deep breath (P = 0.23). Patient satisfaction was superior in S(+)-ketamine-treated patients: 26 (60%) of 44 in the S(+)-ketamine group compared with 16 (35%) of 46 in the placebo group were very satisfied with the analgesic management (P = 0.032). Nausea and vomiting were the most common adverse events, with similar frequencies in both groups. Four patients in the S(+)-ketamine group developed transient hallucinations during the infusion, versus none in the placebo group. In conclusion, small-dose S(+)-ketamine decreased opioid consumption in CABG patients during the first 48 h after surgery.

Aged↗

Behavioral economic analysis of opioid consumption in heroin-dependent individuals: effects of unit price and pre-session drug supply.

Behavioral economic analysis has been used to investigate factors underlying drug consumption in laboratory animals and, increasingly, in human drug abusers. However, there are few studies in heroin abusers, especially those who are not in treatment; such studies may be valuable for understanding the mechanisms of persistent drug use. This study investigated effects of unit price (UP) and pre-session supply of hydromorphone (HYD) on choice and consumption of HYD. Heroin-dependent research volunteers (n=13) stabilized on buprenorphine 8 mg/day completed this eight-session inpatient study. In sessions 1-2, participants sampled two total HYD doses (12 and 24 mg IM) that could be earned in later sessions. In each of the final six sessions, volunteers were given access to a 12-trial choice progressive ratio schedule lasting 3h. On each trial, volunteers could earn a HYD unit dose (1 or 2 mg, for a maximum of 12 or 24 mg, respectively) or money (US dollars 2, for a maximum of US dollars 24). Fixed ratio requirements increased exponentially, generating 24 unit prices for behavioral economic analysis. Before some choice sessions, volunteers could choose (FR 1) to receive extra HYD (12 or 24 mg; at 0915), whereas on other days no supplement was available. HYD choice and peak responding (breakpoint, O(max)) measures increased with unit dose, decreased with pre-session supplements, and were greater among volunteers who used cocaine prior to the experiment. Taking pre-session supplements decreased P(max) and made group-percent HYD consumption more demand-elastic. Consumption was functionally equivalent at differing FR/unit dose combinations. Thus, opioid demand in heroin-dependent individuals not in treatment is a function of drug supply, unit price, and cocaine use.

Adolescent↗

Unit-price analysis of opioid consumption by monkeys responding under a progressive-ratio schedule of drug injection.

Several reports have indicated that drug consumption in self-administration procedures is a function of the ratio of the instrumental requirement to the dose of drug, a quantity termed unit price. We evaluated three predictions from this unit-price model in a reanalysis of data on opioid self-administration in rhesus monkeys responding under a progressive-ratio schedule (Hoffmeister, 1979). We evaluated whether consumption was inversely related to unit price, and compared the goodness of fit of an equation devised by Hursh, Raslear, Shurtleff, Bauman, and Simmons (1988) to that of a linear model predicting consumption as a function of dose. We also tested whether consumption was constant when the same unit price was comprised of different combinations of dose and instrumental requirement. Consumption declined overall as unit price increased. The equation devised by Hursh et al. and the linear model based on dose fit the data equally well. Drug consumption was not uniform at a given unit price. The analyses suggest limits on the unit-price model as a characterization of drug consumption.

Animals↗