An international multidisciplinary consensus statement on the prevention of opioid-related harm in adult surgical patients.

This international multidisciplinary consensus statement was developed to provide balanced guidance on the safe peri-operative use of opioids in adults. An international panel of healthcare professionals evaluated the literature relating to postoperative opioid-related harm, including persistent postoperative opioid use; opioid-induced ventilatory impairment; non-medical opioid use; opioid diversion and dependence; and driving under the influence of prescription opioids. Recommended strategies to reduce harm include pre-operative assessment of the risk of persistent postoperative opioid use; use of an assessment of patient function rather than unidimensional pain scores alone to guide adequacy of analgesia; avoidance of long-acting (modified-release and transdermal patches) opioid formulations and combination analgesics; limiting the number of tablets prescribed at discharge; providing deprescribing advice; avoidance of automatic prescription refills; safe disposal of unused medicines; reducing the risk of opioid diversion; and better education of healthcare professionals, patients and carers. This consensus statement provides a framework for better prescribing practices that could help reduce the risk of postoperative opioid-related harm in adults.

Age is the best predictor of postoperative morphine requirements.

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.

Traditionally, 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.

Epidural catheter tip cultures: results of a 4-year audit and implications for clinical practice.

BACKGROUND AND OBJECTIVES: The aims of this study were to evaluate the clinical relevance of routine microbiological culture of epidural catheter tips after use in acute pain management, and to identify patterns of culture result with respect to both indications for, and duration of, epidural catheterization. METHODS: The Acute Pain Service (APS) reviews all patients under its care at least daily and keeps detailed records on each. Over a 4-year period, when APS protocol required epidural catheter tips to be sent for microbiological culture on removal, the APS saw 1,810 patients who had received epidural analgesia. The records of these patients were reviewed. RESULTS: Culture results were available for 1,443 (79.7%) patients: 1,027 catheter tips (71.2%) were sterile, while 416 (28.8%) were positive for at least 1 type of microorganism. Clinically, no epidural space infections were identified. The highest positive culture rates were found from epidural catheters used in the treatment of pain from fractured ribs or fractured pelves, while the lowest incidences occurred in elective orthopedic and thoracic surgery. The proportion of epidural catheters with positive culture results steadily increased with the duration of catheterization, but there were no clinically significant differences for catheters left in situ for either 3 or 4 days. CONCLUSIONS: We concluded that a significant proportion of epidural catheter tips may be "culture positive" after removal. It is suggested that this probably represents colonization of the skin at the catheter insertion site and subsequent contamination of the catheter tip on removal of the catheter. The large number of "culture positive" tips in the absence of clinically identifiable epidural space infection suggests that routine culture of epidural catheter tips is clinically irrelevant in the vast majority of cases, and that it is not a good predictor of the presence of an epidural space infection.

Costs and consequences: a review of discharge opioid prescribing for ongoing management of acute pain.

Over recent years there has been a growing need for patients to be sent home from hospital with prescribed opioids for ongoing management of their acute pain. Increasingly complex surgery is being performed on a day-stay or 23-hour-stay basis and inpatients after major surgery and trauma are now discharged at a much earlier stage than in the past. However, prescription of opioids to be self-administered at home is not without risk. In addition to the potential for acute adverse effects, including opioid-induced ventilatory impairment and impairment of driving skills, a review of the literature shows that opioid use continues in some patients for some years after surgery. There are also indications that over-prescription of discharge opioids occur with a significant amount not consumed, resulting in a potentially large pool of unused opioid available for later use by either the patient or others in the community. Concerns about the potential for harm arising from prescription of opioids for ongoing acute pain management after discharge are relatively recent. However, at a time when serious problems resulting from the non-medical use of opioids have reached epidemic proportions in the community, all doctors must be aware of the potential risks and be able to identify and appropriately manage patients where there might be a risk of prolonged opioid use or misuse. Anaesthetists are ideally placed to exercise stewardship over the use of opioids, so that these drugs can maintain their rightful place in the post-discharge analgesic pharmacopoeia.

Pain relief and opioid requirements in the first 24 hours after surgery in patients taking buprenorphine and methadone opioid substitution therapy.

The number of patients in buprenorphine opioid substitution therapy (BOST) or methadone opioid substitution therapy (MOST) programs is increasing. If these patients require surgery, it is generally agreed that methadone should be continued perioperatively. While some also recommend that buprenorphine is continued, concerns that it may limit the analgesic effectiveness of full mu-opioid agonists have led others to suggest that it should cease before surgery. However, no good evidence exists for either course of action. Therefore, we undertook a retrospective cohort study comparing pain relief and opioid requirements in the first 24 hours after surgery in 22 BOST and 29 MOST patients prescribed patient-controlled analgesia. There were no significant differences in pain scores (rest and movement), incidence of nausea or vomiting requiring treatment, or sedation between the BOST and MOST patient groups overall, or between those patients within each of these groups who had and had not received their methadone or buprenorphine the day after surgery. There were also no significant differences in patient-controlled analgesia requirements between BOST and MOST patient groups overall, or between patients who did or did not receive MOST on the day after surgery. BOST patients who were not given their usual buprenorphine the day after surgery used significantly more patient-controlled analgesia opioid (P=0.02) compared with those who had received their dose. These results confirm that continuation of buprenorphine perioperatively is appropriate.

Pharmacokinetics of oxycodone after subcutaneous administration in a critically ill population compared with a healthy cohort.

This study aimed to characterise and compare the absorption pharmacokinetics of a single subcutaneous dose of oxycodone in critically ill patients and healthy subjects. Blood samples taken at intervals from two minutes to eight hours after a subcutaneous dose of oxycodone in patients (5 mg) and healthy volunteers (10 mg) were assayed using high performance liquid chromatography. Data were analysed using a non-compartmental approach and presented as mean (SD). Parameters were corrected for dose differences between the groups assuming linear kinetics. Ten patients (eight male, two female) and seven healthy male subjects were included. Maximum venous concentration and area under the concentration curve were approximately two-fold lower in the patient group for an equivalent dose, suggesting either reduced bioavailability or increased clearance: maximum venous concentration 0.14 ± 0.06 vs 0.05 ± 0.02 µg/ml (P <0.0001); area under the concentration curve 19.50 ± 9.15 vs 9.72 ± 2.71 µg/ml/minute (P <0.001) respectively. However, time to maximum venous concentration and mean residence time were not different, suggesting similar absorption rates: time to maximum venous concentration 22.10 ± 18.0 vs 20.50 ± 16.10 minutes (P=0.81); mean residence time 353 ± 191 vs 291 ± 80 minutes (P=0.26). Kinetic parameters were less variable in patients than in volunteers. The patients therefore had reduced exposure to subcutaneous oxycodone. This warrants further model-based analysis and experimentation. Dose regimens for subcutaneous oxycodone developed in healthy volunteers cannot be directly translated to critically ill patients.

Opioids, ventilation and acute pain management.

Despite the increasing use of a variety of different analgesic strategies, opioids continue as the mainstay for management of moderate to severe acute pain. However concerns remain about their potential adverse effects on ventilation. The most commonly used term, respiratory depression, only describes part of that risk. Opioid-induced ventilatory impairment (OIVI) is a more complete term encompassing opioid-induced central respiratory depression (decreased respiratory drive), decreased level of consciousness (sedation) and upper airway obstruction, all of which, alone or in combination, may result in decreased alveolar ventilation and increased arterial carbon dioxide levels. Concerns about OIVI are warranted, as deaths related to opioid administration in the acute pain setting continue to be reported. Risks are often said to be higher in patients with obstructive sleep apnoea. However, the tendency to use the term 'obstructive sleep apnoea' to encompass the much broader spectrum of sleep- and obesity-related hypoventilation syndromes and the related misuse of terminology in papers relating to obstructive sleep apnoea and sleep-disordered breathing remain significant problems in discussions of opioid-related effects. Opioids given for management of acute pain must be titrated to effect for each patient. However strategies aiming for better pain scores alone, without highlighting the need for appropriate monitoring of OIVI, can and will lead to an increase in adverse events. Therefore, all patients must be monitored appropriately for OIVI (at the very least using sedation scores as a '6th vital sign') so that it can be detected at an early stage and appropriate interventions triggered.

Acute pain management in opioid-tolerant patients: a growing challenge.

In Australia and New Zealand, in parallel with other developed countries, the number of patients prescribed opioids on a long-term basis has grown rapidly over the last decade. The burden of chronic pain is more widely recognised and there has been an increase in the use of opioids for both cancer and non-cancer indications. While the prevalence of illicit opioid use has remained relatively stable, the diversion and abuse of prescription opioids has escalated, as has the number of individuals receiving methadone or buprenorphine pharmacotherapy for opioid addiction. As a result, the proportion of opioid-tolerant patients requiring acute pain management has increased, often presenting clinicians with greater challenges than those faced when treating the opioid-naïve. Treatment aims include effective relief of acute pain, prevention of drug withdrawal, assistance with any related social, psychiatric and behavioural issues, and ensuring continuity of long-term care. Pharmacological approaches incorporate the continuation of usual medications (or equivalent), short-term use of sometimes much higher than average doses of additional opioid, and prescription of non-opioid and adjuvant drugs, aiming to improve pain relief and attenuate opioid tolerance and/or opioid-induced hyperalgesia. Discharge planning should commence at an early stage and may involve the use of a 'Reverse Pain Ladder' aiming to limit duration of additional opioid use. Legislative requirements may restrict which drugs can be prescribed at the time of hospital discharge. At all stages, there should be appropriate and regular consultation and liaison with the patient, other treating teams and specialist services.

An audit of intrathecal morphine analgesia for non-obstetric postsurgical patients in an adult tertiary hospital.

We conducted a retrospective audit of adult non-obstetric patients who had received a single dose of intrathecal morphine for postoperative analgesia. These patients were predominantly admitted to a regular postsurgical ward with strict hourly nursing observations, treatment protocols in place and supervision by an Acute Pain Service for the first 24 hours after intrathecal morphine administration. A total of 409 cases were examined for sedation score, incidence of respiratory depression and other side-effects, admission to the high dependency or intensive care unit and opioid-tolerance. Respiratory depression was defined as requiring treatment with naloxone (implying a sedation score of 3 irrespective of respiratory rate), or a sedation score of 2 with a respiratory rate less than six breaths per minute. The patients were predominantly elderly (57.2% were over the age of 70 years) and 84.8% had undergone vascular surgery. Of the total of 409 cases, only one case of respiratory depression was observed. A total of 77 patients were admitted to high dependency or intensive care unit for various reasons including management of postsurgical complications and patient co-morbidities. Our findings suggest that elderly patients who receive intrathecal morphine analgesia can be safely managed in a regular postsurgical ward.

An acute pain service in an Australian teaching hospital: the first year.

The Acute Pain Service began at the Royal Adelaide Hospital in April 1989. Funding, education programmes, policies, procedures, protocols, techniques (particularly patient-controlled analgesia, epidural opioid analgesia and subcutaneous morphine therapy) and daily organisation of the service are described in this article, and the experience with the 1053 patients referred to the Service during the first year of operation is reported. The occurrence of major complications was small. Mild-to-moderate respiratory depression occurred in four (0.5%) of the 747 patients who received patient-controlled analgesia and in none of the 177 who received epidural opioids. Five patients receiving patient-controlled analgesia had persistent nausea/vomiting; 320 (35%) of all patients receiving patient-controlled analgesia or epidural opioids suffered nausea/vomiting that required no treatment or was alleviated by treatment with an antiemetic. Around 13% of patients reported mild-to-moderate itching. In our experience, the combination of appropriately trained nursing and medical staff, standardised orders and procedures, and proper supervision can lead to safe, more effective management of acute pain.

Norpethidine toxicity and patient controlled analgesia.

Patient-controlled analgesia (PCA) with i.v. opioids is prescribed increasingly. We report three cases of norpethidine toxicity in patients receiving pethidine by PCA.

Effect of meperidine on oxygen consumption, carbon dioxide production, and respiratory gas exchange in postanesthesia shivering.

Meperidine has been used to suppress postanesthesia shivering. However, its efficacy to date has only been assessed by observation of visible shivering. We measured the effect of meperidine on oxygen consumption (VO2), carbon dioxide production (VCO2) and pulmonary gas exchange in 14 otherwise healthy patients shivering after general anesthesia. Meperidine successfully suppressed visible shivering in all patients and was associated with significant decreases in VO2, and VCO2 and minute ventilation (VE) but not with return to basal levels. Arterial PCO2 levels remained unchanged at normal, whereas significant improvements occurred in pH and bicarbonate levels. Meperidine is an effective method of reducing the elevated metabolic demand of shivering.

The effects of airway impedance on work of breathing during halothane anesthesia.

Humidifiers and small diameter endotracheal tubes placed in the airway circuit increase the impedance to breathing. The effect of such impedances on the work of breathing and respiratory patterns was studied in eight healthy adult patients (60-80 kg) anesthetized with 1 and 2 MAC halothane in oxygen. A Cascade Humidifier and Portex Humid-Vent (dry and water saturated) were evaluated while patients breathed through an 8.0-mm endotracheal tube. A 6.0-mm endotracheal tube was also assessed without the humidifiers. At 1 MAC the Cascade Humidifier and the wet Humid-Vent when used with the 8.0-mm tube increased the work of breathing to 86.8 ml and 76.8 ml, 77% and 70% above baseline levels of 48.1 ml, whereas the 6.0-mm tube without the humidifiers increased work 89% to 78.9 ml. Tidal volume and respiratory frequency were unchanged throughout the study, although inspiratory time was prolonged. Lightly to moderately anesthetized healthy adult patients are able to maintain minute ventilation despite the impedance associated with commonly used humidifiers by significantly increasing work of breathing.

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.

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.