Pamela E. Macintyre

Age is the best predictor of postoperative morphine requirements

&NA; The dose of opioid prescribed for postoperative pain relief has traditionally been based on the weight of the patient. Although a reduction in dose is often suggested for elderly patients over 70 years of age, age‐related alterations to dose are generally not considered for younger patients. The records of 1010 patients, under 70 years old, prescribed morphine via patient‐controlled analgesia (PCA) after major operations were examined to see what factors might best predict the amount of morphine used in the first 24 h after surgery. Factors included were age, sex, weight, operative site, verbal numeric pain score (at rest and on movement) and a nausea/vomiting score. In a subgroup of 78 of these patients, the effects of intraoperative and recovery room doses of opioid (‘clinical’ loading dose) were analysed. Although the interpatient variability in PCA morphine doses was large (differences of up to 10‐fold in each age group), the best predictor of PCA morphine requirement in the first 24 h after surgery (the amount required in the 24 h after the initial loading dose) was the age of the patient. An estimate of these requirements for patients over the age of 20 years can be obtained from the formula: average first 24 h morphine requirement (mg) = 100 − age. PCA allows patients the flexibility to titrate their own opioid dose; if conventional analgesic regimens are to become more effective, they too need to allow for the wide interpatient variation in dose requirements. Although previous studies have noted a correlation between patient age and the amount of opioid needed, this study quantifies this correlation and provides guidelines for opioid dosing. Prescriptions for conventional analgesic regimens should include a dose range centred on values obtained from the above formula to allow for the large interpatient variation in each age group. While initial morphine dose should be guided by patient age and not weight, subsequent doses must still be titrated according to effect.

Pharmacokinetic Optimisation of Opioid Treatment in Acute Pain Therapy

SummaryTraditionally, opioids have been administered as fixed doses at fixed dose intervals. This approach has been largely ineffective. Patient-controlled analgesia (PCA) and upgraded traditional approaches incorporating flexibility in dose size and dose interval, and titration for an effect in individual patients with the monitoring of pain and sedation scores, can greatly improve the efficacy of opioid administration. Optimising opioid use, therefore, entails optimising the titration process.Opioids have similar pharmacodynamic properties but have widely different kinetic properties. The most important of these is the delay between the blood concentrations of an opioid and its analgesic or other effects, which probably relate to the delay required for blood and brain and spinal cord (CNS) equilibrium. The half-lives of these delays range from approximately 34 minutes for morphine to 1 minute for alfentanil. The titration is influenced by the time needed after an initial dose before it is safe to administer a second dose and the duration of the effects of a single dose, which varies widely between opioids, doses and routes of administration. To compare opioids and routes of administration, we examined the relative CNS concentration profiles of opioids — the CNS concentration expressed as a percentage of its maximum value. The relative onset was the defined as the time the relative CNS concentration first rose to 80% of maximum, while the relative duration was defined as the length of time the concentration was above 80%. For an intravenous bolus dose, the relative onset varies from approximately 1 for alfentanil to 6 minutes for morphine, while their relative durations are approximately 2 and 96 minutes, respectively.Although all of the common opioids, perhaps with the exception of alfentanil, have kinetic and dynamic properties suitable for use in PCA with intravenous bolus doses, the long relative duration of morphine makes it particularly suited to an upgraded traditional approach using staff administered intramuscular or subcutaneous doses. There is a clear kinetic preference for regimens with a rapid onset and short duration (e.g. intravenous PCA) for coping with incident pain. It is shown that, in general, titration is improved by the more frequent administration of smaller doses, but it is important to use additional doses to initially ‘load’ a patient. The titration of opioids should always be accompanied by the monitoring of pain and sedation scores and ventilation.

Morphine blood concentrations in elderly postoperative patients following administration via an indwelling subcutaneous cannula.

The pharmacokinetics of morphine in venous blood after a 5 mg bolus dose via an indwelling subcutaneous cannula were characterised in 22 elderly patients undergoing elective major surgery. In a subgroup of seven patients, the kinetics were also characterised after a second 5 mg dose of morphine administered 180 min after the first dose. Blood morphine concentrations following the single dose were highly variable — the coefficients of variation of Cmax, Tmax and the AUC up to 180 min (AUC180) were 54, 37 and 39%, respectively, with mean values of 86.6 ng.ml−1, 15.9 min and 3954 ng.ml−1, respectively. These mean values for the second dose were not statistically different to those of the first dose but were more variable. It was concluded that the injection of morphine via an indwelling subcutaneous cannula results in blood concentrations that are comparable to, and as variable as, those arising from intramuscular injection.

Advances in analgesia in the older patient

The average age of the worlds population is increasing rapidly, with those over 80 years of age the fastest growing subsection of older persons. Consequently, a higher proportion of those presenting for surgery in the future will be older, including greater numbers aged over 100 years. Management of postoperative pain in these patients can be complicated by factors such as age and disease-related changes in physiology, and disease-drug and drug-drug interactions. There are also variations in pain perception and ways in which pain should be assessed, including in patients with cognitive impairment. Alterations in pharmacokinetics and pharmacodynamics may influence drugs and techniques used for pain relief. The evidence-base for postoperative pain management in the older population remains limited. However, most commonly used analgesic regimens are suitable for older patients if adapted and titrated appropriately.

Pharmacokinetics of fentanyl after subcutaneous administration in volunteers

Background and objective Pain relief using intermittent subcutaneous injections of an opioid (e.g. morphine) avoids the need for venous access and does not require complex or expensive pumps and devices. Although data on the pharmacokinetics of subcutaneous morphine exist, there are no comparable data for fentanyl in healthy volunteers. Therefore, the aim of this study was to characterize the pharmacokinetics of 200 μg fentanyl administered as a single bolus dose via the subcutaneous route in healthy opioid-naive volunteers. Methods Nine healthy male volunteers were given 200 μg of subcutaneous fentanyl for more than 30 s. Opioid effects were blocked by administration of naltrexone. Venous blood samples taken at intervals from 5 min to 10 h after the dose were assayed using a liquid chromatography-mass spectrometry method. Pharmacokinetic data were analysed using a noncompartmental analysis approach. Results After subcutaneous bolus dose administration, the median maximum concentration of fentanyl was 0.55 ng ml−1 (range 0.28–0.87 ng ml−1), reached at a median time of 15 min (range 10–30 min). The terminal half-life was 10.00 h (range 5.48–16.37 h). Conclusion Absorption of subcutaneous fentanyl was relatively rapid and similar to the rate of absorption previously reported for subcutaneous morphine; the terminal half-life for fentanyl was substantially longer (10 h) than that of morphine (2.1 h), and blood concentrations were no more variable than that after administration by other nonintravenous routes.

The scientific evidence for acute pain treatment

Purpose of review The quantity and quality of evidence available for the management of acute pain has grown rapidly over the last 20 years. Rather than listing current evidence related to specific acute pain treatments, the purpose of this review is to look at recent evidence in terms of its availability and ease of access, synthesis and incorporation into clinical practice as well as some of its limitations. Recent findings An increasing number of evidence-based medicine tools are available to assist clinicians in the provision of acute pain treatments. However, integration of this population-based evidence with clinical expertise, different patient factors and resource availability in different practice settings is still required if the best outcome is to be achieved for each patient. Summary It is difficult for clinicians to remain updated and synthesize all the evidence available relating to the treatment of acute pain. Assistance is available, but there may be limitations to some of the evidence presented and its application to different aspects of clinical practice and different patient groups.

A mixture of alfentanil and morphine for rapid postoperative loading with opioid: theoretical basis and initial clinical investigation.

Pharmacokinetic modelling of estimated central nervous system concentrations was used to devise the optimal mixture of morphine and alfentanil for the treatment of postoperative pain. Modelling revealed that an intravenous opioid pain protocol using an alfentanil−morphine mixture in the proportions 0.75 : 10 mg would provide a profile of analgesia of rapid onset, yet slow offset. The regimen was evaluated in 58 patients in the recovery ward who were randomly allocated to receive analgesia using pain protocols with either morphine or the mixture. Groups were well matched for age, weight and initial pain scores. The mean (SD) time to patient comfort was 27.6 (20.2) min for the mixture and 41.2 (18.6) min for morphine (p = 0.01). Multiple regression analysis revealed that that initial pain score (p = 0.009) and drug group (p = 0.02), but not age, weight or gender were independent predictors of the time to comfort. Drug group was not a significant predictor of adverse effects.

Pharmacokinetics of subcutaneous morphine in the elderly postoperative patient

intramuscular route. There has been a recent resurgence of interest in the subcutaneous route for oplokis given for the management of both cancer and postoperative pain. However, there is very IiMle lnfoimatlon about the klnetlcs bf morphine uptake from subcutaneous tissues, particularly in the elderly. AIM: To determine the absorption kinetics of a single bolus of morphine from infraclavicular subcutaneous tissue so that a “lockout” interval for subcutaneous titration of morphlne or the use of a subcutaneous patlent controlled at&g&a (PCA) system could be ldentlfled. METHOD: Ten patients aged 60-89years werestudied onthefirstpostoperativedayfdlawing majorabdominal surgery. Morphine was not used in the perloperatlve period prior to cornof the study. pain r&f was by Intravenous pethldlneadminlstered vla a PCAsystem. The study commenced onthefirst p&epera&e mornlng.A23g ‘butt* needle was inserted into the infradavlcdar subcutaneous tissue and a single 5 mg b&d&e of morphine Injected. Blood samples were collected from a catheter with its tlo In the subclaan vain at wedetermkted in@&s: 2.5, 5.7.5.10. 15, 20, Xl,45 and 60 minutes (mins), every 30 minutes to’120 mlns and hourly ther&fter to six hours. Samples~w&e &&g using a solvent extraction technique, high pressure liquid chromatography and an ekctmhmtcal detector. RESULTS: One patlent exhibited an extremely hlgh peak blood concentratton (Cmax) of 406 ng/ml at 5 mins. This is con&tent wlth Inadvertent Intravenous admlnistratlon. In the remalnlng 9 subjects the time to maximal blood concentration (Tmax) ranged from 10 to 30 mlns with 70% of peak values occurrlng within 20 r&s. of lnjectlon. Cmax in these 9 patients varled four fdd (mean 67, sd 31.4; range 31 to 125 ng/ml) CONCLUSIONS: A ‘lockout” interval of 30 minutes is suggested by these data for PCA or repeated doses of morphine via the subcutaneous route. This wWM allow flexible and safe postoperative analgesia without the requirement for an intravenous cannula. These encouraging results in the elderly have provided the stimulus to now examlne the kinetics of single doses of morphlne in children and young adults and of repeated doses in children, young adults and the elderly. Titration of morphine via a fine indwelling subcutaneous cannula would provide safe, flexible, effective analgesia at vary low cost as long as the patients were observed for 5 mins after injection.

Morphine requirements in the postoperative patient using PCA decrease with age but are unrelated to weight

maintenance requirements and the ages and welgMs of petfents to ascertain if either variable would be useful in determining the starting dose of opbld for the postoperative ward management of pain. METNODS: The records of 62 consecutfve patients aged 22 to 96 were studied. All patients had been admitted to the highdependency postoperative ward after surgery. Two patbnts who had recefved regular opbld analgesfa preoperatively were exduded. All postoperative patienta requiring analgesia in the recovery ward routinely received indivkluafly titrated loading doses of opbkf before PCA was commenced. Pain relief was routinely assessed each day using a verbal numerical pain score (0 = no pain, 10 = the worst pain Imaginable). The cumulatfve maintenance morphine requirements for the first 24 hours were then analysed with respect to patient age and weigM.

Comparison of Dextropropoxyphene and Paracetamol with Paracetamol After Third Molar Dental Extractions

Background: Single‐dose studies comparing the analgesic efficacy of dextropropoxyphene and paracetamol with paracetamol have usually found equi‐analgesic effect. Whether this phenomenon is also so after multiple doses is uncertain.