Patient controlled analgesia used to assess the efficacy and potency of a new opioid

Patient controlled analgesia (PCA) is widely used for the management of postoperative pain. PCA also permits a comparison to be made among analgesics in the clinical setting because it limits the variability introduced by third parties. Use of PCA to establish efficacy and potency data for an investigational drug, pentamorphone, compared with morphine is reported. Pentamorphone was found to be more efficacious than morphine in the first hour after surgery because significantly more patients were able to achieve a visual analogue scale of less than 30 mm with pentamorphone. Thereafter pentamorphone and morphine were found to be equally efficacious. Initially pentamorphone may be more potent than morphine based on the greater volume of morphine used in the first hour of therapy. However, a potency ratio could not be determined because this result was under conditions of unequal analgesia. The potency ratio determined at 24 h of therapy under equianalgesic conditions (252:1) is similar to previously reported potency data from laboratory studies (200:1). This study supports the use of PCA as a model to investigate and compare new drugs to establish their efficacy and potency.

P atient controlled analgesia (PCA) is widely used for the man- agement of postoperative pain and is highly effective in providing adequate pain relief (1,2).With appropriate choice of opioid doses and lockout intervals, patients using PCA can obtain pain relief regardless of the specific pharmacodynamic and pharmacokinetic properties of the opioids chosen (3-5).Thus PCA should be useful as a research tool to compare opioids (6,7).Efficacy can be studied through determination of the degree of pain relief obtainedusing a visual analogue scale (VAS) -with each analgesic at various time points.Further, under equianalgesic conditions with PCA, an estimate of relative potency can be made between two opioids through a comparison of the total amount of opioid used.
We present the results of efficacy and potency determination using PCA with a new drug, pentamorphone, versus morphine, after lower abdominal surgery.Pentamorphone (14-beta-npentylaminomorphinone) is a morphine derivative with a high lipophilicity and fairly stable cardiovascular effects (8,9).In animal studies pentamorphone had a shorter onset and duration than morphine (10).With these properties, pentamorphone is expected to be a useful drug for PCA.

PATIENTS AND METHODS
After institutional review board approval at Duke University Medical Center, written informed consent was obtained from 60 patients scheduled to undergo lower abdominal surgery (exploratory laparotomy, abdominal hysterectomy, oophorectomy, etc).Only American Society of Anesthesiologists physical status I or II patients between 20 and 69 years who were within 20% of their ideal body weight were considered for this study.Patients were excluded if they had received a general anesthetic during the preceding month or were on any opioid medication during the month before surgery.
Patients underwent standardized education on the use of the Abbott Lifecare PCA (Illinois).The pamphlet details that patients should use the PCA expectantly and keep their pain level at a manageable, mild level was emphasized.In addition, education served to allay potential fears or social mores regarding the use of a PCA machine.As a part of the process, patients were instructed on how to complete a linear VAS (on a scale of 1 to 100).
Patients were randomly assigned, in a double-blind fashion, to one of two groups.Twenty patients received morphine and the other 40 received pentamorphone for postoperative analgesia.The potency of pentamorphone has previously been determined in a laboratory setting with human volunteers (9).The data from this study were used to derive the initial dosing for pentamorphone compared with morphine.Estimated equipotent doses of morphine (1 mg/mL) and pentamorphone (5 mg/mL) were prepared for the PCA pump by the pharmacy.
Anesthesia was standardized to include thiopental, 60% to 70% nitrous oxide and isoflurane supplemented with less than 6 mg/kg fentanyl as necessary to maintain adequate anesthesia.Vecuronium was used for neuromuscular blockade and was antagonized with neostigmine and glycopyrrolate at the end of the procedure.
In the postanesthesia care unit (PACU) a loading dose of 0.04 mL/kg of the randomized analgesic was administered via an Abbott Lifecare PCA.This translated into either 40 mg/kg morphine or 0.2 mg/kg pentamorphone.This loading dose of opioid was given when a VAS greater than 50 mm was recorded by the patient, and was repeated up to three times for a VAS greater than 50 mm while in the PACU.If these loading doses provided inadequate analgesia, patients were excluded from the study and conventional analgesia was started.PCA settings were standardized to a maintenance dose of 0.02 mL/kg and a lockout interval of 8 mins.Patients were discharged from the PACU to a routine postoperative floor when awake with a satisfactory level of analgesia.A VAS (completed by the patient), sedation scale and side effects (completed via observation and open questions) were recorded at 10, 20 and 30 mins and at 1, 4, 8, 12, 16, 20 and 24 h.
Analysis of variance for repeated measures was used for comparison between the groups.The Mann Whitney U test was used for comparison of nonparametric data.P<0.05 was considered significant.Results are given as a mean ± SD.

RESULTS
The two groups showed no differences in age, height or weight, duration of surgical procedure and total amount of intraoperative fentanyl used (Table 1).Initial VAS scores showed no statistical difference before the first loading dose of pentamorphone (81±18 mm) or morphine (83±18 mm).The VAS following the initial loading dose of pentamorphone (51±31 mm) and morphine (63±32 mm) showed no statistical difference.However, the VAS was significantly lower at 20, 30 and 60 mins in the pentamorphone group compared with the morphine group (P<0.05)(Figure 1).The percentage of patients who received pentamorphone with a VAS less than 30 mm was significantly greater than the percentage of

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PAIN RES MANAGE VOL 1 NO 4 WINTER 1996 Ginsberg et al those who received morphine at 10, 20 and 30 mins, and 1 and 4 h (P<0.05)(Figure 2).The cumulative volume of opioid used in each time period is depicted in Figure 3.During the initial period, patients in the pentamorphone group used less volume versus patients in the morphine group.This difference was statistically significant at 10, 20 and 30 mins (P<0.05).By 4 h, patients in both groups used equal volumes of opioid.After 24 h, the total volume of analgesic used was 62.9±27.9mL in the morphine group and 50±30.1 mL in the pentamorphone group.
An estimated potency ratio can be derived from the total 24 h volumes of analgesic used.For morphine, 62.9 mL equals 62900 mg of morphine and for pentamorphone 50 mL equals 250 mg of pentamorphone.The ratio of morphine to pentamorphone used is approximately 252:1, which represents an potency ratio as it was derived under equianalgesic conditions.There was no difference between the groups in the level of sedation or side effects (Table 2).Fifteen per cent of the patients in the morphine group and 20% of the patients of the pentamorphone group (difference was not significant) were excluded in the PACU because adequate analgesia could not be obtained with the three allowed loading doses.

DISCUSSION
PCA has been proposed to be a useful research tool to determine the efficacy of various agents and modes of therapy for pain (6,7).In this investigation we used the modality of intravenous PCA to determine efficacy and potency data about a new opioid, pentamorphone, compared with morphine.
The value of PCA as a research tool is partly due to the limitations of some of the alternate methods used to compare analgesics.For example, minimum effective analgesic concentration (MEAC) is determined by measuring opioid concentration just before the request for additional analgesia.It is an accurate method to determine the potency of various opioids but is cumbersome in the clinical setting.Alternatively, electroencephalograms (EEGs) have been used to compare opioids and determine potency ratios (11).The relative potency for analgesia of an opioid may parallel the relative potency to produce a given EEG effect, but the use of EEG is only theoretical.Unfortunately, no measure of an EEG change has correlated with pain or relief of pain.Another technique to evaluate relative opioid potency is to determine the opioid concentration required to produce a 50% minimum anesthetic concentration (MAC) of an inhalational agent (12).Although this is an objective measurement, it is a measure of anesthesia of which pain is only a component.
This study was designed as a fixed dose analgesic comparison study that used PCA to eliminate the need for a third party to respond to patient request for pain medication.Further, multiple fixed doses over 24 h were observed, allowing comparison of analgesic efficacy and potency at various points after surgery and allowing patients to titrate the analgesic individually to their pain needs.This study design is in contrast to classic single dose analgesic studies, in which a single dose of a test drug is compared with placebo and a positive control drug for several hours after administration (13-15).Although single dose studies allow the comparison of analgesics at a given time, a study using PCA should allow for a more meaningful comparison of analgesic agents over a clinically relevant postoperative time period.
Using PCA, we compared time to onset of pain relief, amount of pain relief obtained and total volumes of analgesic used, starting with fixed doses calculated from the laboratory-determined potency ratio of 200:1 (9).Adjustment for the standardized size of the loading doses and the PCA bolus doses should have been made by patients, who were freely allowed to administer opioids every 8 mins.
Pentamorphone demonstrated a faster onset of analgesia and a greater degree of analgesia compared with morphine in the first 60 mins of therapy as determined by lower VAS scores (Figures Figure 3) Cumulative volume of opioid used in each time period

TABLE 1 Demographics and total fentanyl used
Figure 1) Bar graph representing visual analogue pain scale comparing pentamorphone with morphine.*P<0.05