John L. Plummer

Fentanyl blood concentration-analgesic response relationship in the treatment of postoperative pain.

The inter-and intrasubject variability in blood concentration-analgesic response relationship for fentanyl were investigated using the technique of patient-controlled analgesia (PCA) in30 consenting patients scheduled for surgical procedures involving an abdominal incision (15 upper and 15 lower abdominal incisions). All patients had a thiopental, nitrous oxide/oxygen, pancuronium anesthetic with 200 μg fentanyl intraoperatively. Postoperative pain relief was providedwith fentanyl from a Janssen On-Demand Analgesic Computer (ODAC) set to provide a basal infusionrate of 20 μg/hr, a bolus “demand” dose of 20 μg, and a lockout period of 5 minutes. Frequent blood samples were collected immediately before patients demanded doses, and these were taken asan estimate of the minimum effective concentration (MEC). A mean of 22 samples (range 12 to 45) were collected per patient over a mean study duration of 50 hours (range 24 to 72). The patients required larger hourly fentanyl doses in the first 6-hour period (83.9 ± 30.1 μg/hr) than in any other 6-hour period (mean values varied from 37.3 to 63 pg/hr). The mean (± SD) hourly fentanyl dose rate and total cumulative dose were 55.8 ± 22 μg/hr (range 28.8to 136 μg/hr) and 2739 ± 1191 μg (range 900 to 6260 μg), respectively. The mean (± SD) MEC was 0.63 ± 0.25 ng/ml (five-fold range from 0.23 to 1.18) and the mean intrapatient coefficient of variation in MEC was 30.2% (range 16 to 46%). The MEC values remained relatively constant in all patients over the 48-hour study period. The small intrapatient variation in MEC over the study period supports a relationship between blood fentanyl concentration and the extent of pain relief. Therefore, the large fluctuations in the hourly fentanyl dose rate do not accurately reflect the relatively constant blood concentration-analgesic effect relationship. These data emphasize the care necessary in the use of mean hourly fentanyl dose requirements as derived from PCA infusions as indexes of pharmacodynamic effects, especially pain relief. A similarsituation may exist for the other opioids used in PCA infusion pumps. Psychological factors werefound to have some predictive value for MEC and maintenance dose requirements.

Preference for place of care and place of death in palliative care: are these different questions?

Place of death is at times suggested as an outcome for palliative care services. This study aimed to describe longitudinal preferences for place of care and place of death over time for patients and their caregivers. Longitudinal paired data of patient/caregiver dyads from a prospective unblinded cluster randomised control trial were used. Patients and caregivers were separately asked by the palliative care nurse their preference at that time for place of care and place of death. Longitudinal changes over time for both questions were mapped; patterns of agreement (patient and caregiver; and preference for place of death when last asked and actual placed of death) were analysed with kappa statistics. Seventy-one patient/caregiver dyads were analysed. In longitudinal preferences, preferences for both the place of care (asked a mean of >6 times) and place of death (asked a mean of >4 times) changed for patients (28% and 30% respectively) and caregivers (31% and 30%, respectively). In agreement between patients and caregivers, agreement between preference of place of care and preferred place of death when asked contemporaneously for patients and caregivers was low [56% (κ 0.33) and 36% (κ 0.35) respectively]. In preference versus actual place of death, preferences were met for 37.5% of participants for home death; 62.5% for hospital; 76.9% for hospice and 63.6% for aged care facility. This study suggests that there are two conversations: preference for current place of care and preference for care at the time of death. Place of care is not a euphemism for place of death; and further research is needed to delineate these. Patient and caregiver preferences may not change simultaneously. Implications of any mismatch between actual events and preferences need to be explored.

Pharmacokinetics of fentanyl in lumbar and cervical CSF following lumbar epidural and intravenous administration

&NA; Fentanyl (1 &mgr;g/kg body weight) was administered intravenously and via a lumbar epidural catheter (in random order) on 2 separate occasions to 6 patients with chronic pain associated with non‐terminal disease states. Frequent blood samples were collected from an indwelling intravenous catheter and CSF samples were collected via spinal needles inserted in the cervical (C7‐T1 interspace) and lumbar (L3,4 interspace) regions at 0, 5, 10, 20, 30 and 45 min after fentanyl administration. The concentration of fentanyl in blood and CSF samples were quantified by a sensitive and selective gas‐liquid chromatography assay. Visual analogue pain scores (VAPS) were recorded every 5 min for the first hour. Coded syringes (one containing the appropriate fentanyl dose while the other contained an equivalent volume of saline) allowed the investigator administering the fentanyl and assessing VAPS to remain blinded as to which route of administration actually contained the fentanyl. There was minimal vascular uptake of fentanyl following epidural administration. Similarly, the permeation of fentanyl into cervical and lumbar CSF following intravenous administration was minimal and erratic such that only 4 of the 60 CSF samples had detectable fentanyl concentrations. In contrast, there was a rapid penetration of fentanyl across the dura mater following lumbar epidural administration. There was significantly fentanyl in lumbar CSF samples by 10 min in 5 patients, and by 20 min in all 6 patients. The mean maximum lumbar CSF concentration was 19.1 ng/ml, while the time associated with these maximum concentrations was 22.5 min. The mean maximum cervical CSF fentanyl concentrations were 10% of the lumbar CSF concentrations. Cervical CSF fentanyl concentrations exceeded 0.5 ng/ml in only 2 of the 6 patients. There was no consistent similarity between the VAPS and time with the two routes of fentanyl administration. However, VAPS always decreased following epidural administration. It is concluded that fentanyl is rapidly absorbed across the dura mater following epidural administration providing significant lumbar CSF concentrations. The fentanyl in lumbar CSF undergoes cephalad migration, albeit to a small extent, as a result of passive CSF flow. The high lumbar CSF fentanyl concentrations interact with the opioid receptors in the dorsal horn region of the spinal cord to provide pain relief. However, the role of cervical fentanyl concentrations to any pharmacological effects remains unresolved.

Variables of patient-controlled analgesia 2. concurrent infusion

The effectiveness of morphine after surgery by patient‐controlled analgesia alone or with a concurrent infusion was studied. The infusion did not reduce the dose of self‐administered analgesic and patients treated in this way received twice as much drug as those who used patient‐controlled analgesia alone. Pain control was similar in both groups. The practice of patient‐controlled analgesia plus infusion requires critical review.

Prescribing in palliative care as death approaches.

OBJECTIVES: To determine how prescribing for comorbid illnesses and symptom control changes during the palliative phase of a terminal illness.

Variables of patient‐controlled analgesia 1. bolus size

The efficacy of a range of demand doses of morphine for patient‐controlled analgesia was studied. Patients who self–administered the smallest dose (0.5 mg) were frequently unable to achieve good pain control; patients who received the largest dose (2 mg) had a high incidence of ventilatory depression. A dose of 1 mg was the best increment under the conditions of this study but the relationship between increment and lockout interval requires consideration.

The transdermal administration of fentanyl in the treatment of postoperative pain: pharmacokinetics and pharmacodynamic effects

&NA; A transdermal formulation of fentanyl (TTS‐fentanyl, Alza Corp., Palo Alto, CA) was evaluated in 13 surgical patients after an abdominal operation. An intraoperative dose of fentanyl (100–200 &mgr;g i.v.) was administered at the same time as the TTS‐fentanyl systems (50–125 &mgr;g/h) were applied to the antero‐lateral chest wall. The TTS‐fentanyl systems remained in situ for 24 h and were then removed and a second lot of systems were applied to the contra‐lateral chest wall. There was a mean (S.D.) delay time of 12.7 (9.6) h before minimum effective blood fentanyl concentrations (MEC) were obtained from the systems and pseudo‐steady state was reached between 36 and 48 h. There was a decay time of 16.1 (7.1) h after the systems were removed for the blood fentanyl concentration to decrease to less than the mean MEC for the control of postoperative pain. There was marked variability between patients in the actual hourly fentanyl dose rate determined from the residual amount of fentanyl remaining in the system and the duration of application. Significantly more supplementary pethidine was administered for inadequate postoperative analgesia between 0 and 12 h compared to the 12–24, 24–36 and 36–48 h periods; this was consistent with the observed delay time. Three patients required a reduction in the hourly fentanyl dose rate because of bradypnoea while 1 patient required an increase in dose because of inadequate pain relief. Nausea was the most frequently reported side effect (85% of patients) while bradypnoea, drowsiness, unpleasant dreams and headache were also reported. These effects were due to the combined effects of a sustained blood fentanyl concentration and the intermittent supplementary pethidine doses. Side effects due to the topical formulation were transient and included erythema (8 patients) and a minor rash (2 patients) in the area occluded by the systems. The TTS‐fentanyl systems provided a significant contribution to postoperative pain control but, at the TTS dose rates used, supplementary doses of pethidine were required by all patients probably to control ‘incident’ pain.

Randomized, Double-Blind, Placebo-Controlled Study to Assess the Efficacy and Toxicity of Subcutaneous Ketamine in the Management of Cancer Pain

PURPOSE The anesthetic ketamine is widely used for pain related to cancer, but the evidence to support its use in this setting is weak. This study aimed to determine whether ketamine is more effective than placebo when used in conjunction with opioids and standard adjuvant therapy in the management of chronic uncontrolled cancer pain. Ketamine would be considered of net benefit if it provided clinically relevant improvement in pain with limited breakthrough analgesia and acceptable toxicity. PATIENTS AND METHODS In this multisite, dose-escalation, double-blind, randomized, placebo-controlled phase III trial, ketamine or placebo was delivered subcutaneously over 3 to 5 days. RESULTS In all, 185 participants were included in the primary analysis. There was no significant difference between the proportion of positive outcomes (0.04; 95% CI, -0.10 to 0.18; P = .55) in the placebo and intervention arms (response rates, 27% [25 of 92] and 31% [29 of 93]). Pain type (nociceptive v neuropathic) was not a predictor of response. There was almost twice the incidence of adverse events worse than baseline in the ketamine group after day 1 (incidence rate ratio, 1.95; 95% CI, 1.46 to 2.61; P < .001) and throughout the study. Those receiving ketamine were more likely to experience a more severe grade of adverse event per day (odds ratio, 1.09; 95% CI, 1.00 to 1.18; P = .039). The number of patients needed to treat for one additional patient to have a positive outcome from ketamine was 25 (95% CI, six to ∞). The number needed to harm, because of toxicity-related withdrawal, was six (95% CI, four to 13). CONCLUSION Ketamine does not have net clinical benefit when used as an adjunct to opioids and standard coanalgesics in cancer pain.

Long-term spinal administration of morphine in cancer and non-cancer pain: a retrospective study

&NA; Records of 313 patients who had been treated with spinal morphine via an implanted Port‐A‐Cath were reviewed. In 284 cases the Port‐A‐Cath was implanted for epidural delivery of morphine in patients with cancer‐related pain. These patients were treated for a mean of 96 (range 1–1215) days. There was a wide variation in dose requirements, minimum daily dose ranging from 0.5 to 200 mg and maximum daily dose from 1 to 3072 mg. However, there was no clear trend to increasing dose as period of epidural morphine administration increased. The most frequent complications were pain on injection (12.0% incidence), occlusion of the portal system (10.9%), infection (8.1%) and leakage of administered morphine such that it did not all reach the epidural space (2.1%). In all but 1 case infections were limited to the area around the portal or along the catheter track. All infections resolved without sequelae following removal of the portal and/or administration of antibiotics. In 17 patients Port‐A‐Caths were implanted for the intrathecal delivery of morphine to control cancer‐related pain. These patients also exhibited wide variations in morphine dose requirements. Port‐A‐Caths were also implanted for delivery of spinal morphine in 12 patients with chronic pain which was not related to cancer and which failed to respond to other therapies. These patients were treated for a mean of 155 (range 2–575) days. Port‐A‐Caths were removed from 7 of these patients, primarily due to infection (2 cases) and inadequate pain relief and pain on injection (2 cases).

Estimation of methadone clearance: application in the management of cancer pain

&NA; The long half‐life and wide inter‐patient variability in clearance of methadone make this drug difficult to use optimally. If a patients methadone clearance is known, however, dose regimens can be devised to maintain any desired blood concentration and hence, since the effect of methadone is related to its concentration in the blood, pain relief. We investigated methods for determining methadone clearance. In 25 patients, clearance was estimated by monitoring blood methadone concentrations following an intravenous infusion. Estimates of clearance adequate for clinical purposes could be obtained by assaying only 10–12 blood samples collected over 30 h following the infusion. The blood sampling schedules were such that it was not necessary to collect samples during the night, so the procedure could be done on an outpatient basis. An advantage of this procedure is that it also allows estimation of the blood methadone concentration required to relieve pain. We also conducted a retrospective study of data from 185 patients whose methadone clearance we had determined, to identify factors which may give rise to the large inter‐patient variation in clearance. Clearance tended to be high in patients taking phenytoin, spironolactone, verapamil or oestrogens, and low in patients taking amitriptyline. Patients with malignant disease as opposed to chronic benign pain, and patients 65 years of age or older, tended to have low clearance. Clearance was positively associated with haematocrit. An equation was constructed allowing methadone clearance to be predicted from knowledge of these factors. The predicted clearance, however, showed only a moderately strong correlation with measured clearance (r = 0.75), indicating that factors not investigated also had a major influence on methadone clearance.