ORIGINAL ARTICLE Patient controlled analgesia used to assess the efficacy and potency of a new opioid Brian Ginsberg MD, Katherine P Grichnik MD, Margaret Muir RN BSN, Michael Damask MD, Peter S Glass MD B Ginsberg, KP Grichnik, M Muir, M Damask, PS Glass. Contrôle de l’analgésie par les patients pour Patient controlled analgesia used to assess the efficacy and po- évaluer l’efficacité et la puissance d’un tency of a new opioid. Pain Res Manage 1996;1(4):227-231. nouvel opioïde RÉSUMÉ : Le contrôle de l’analgésie par les patients (CAP) est gran- Patient controlled analgesia (PCA) is widely used for the manage- dement utilisé dans la prise en charge de la douleur postopératoire. Le ment of postoperative pain. PCA also permits a comparison to be CAP permet aussi de comparer différents analgésiques dans un con- made among analgesics in the clinical setting because it limits the texte clinique parce qu’il limite la variabilité introduite par les tiers. variability introduced by third parties. Use of PCA to establish effi- L’utilisation du CAP en vue d’établir des données sur l’efficacité et la cacy and potency data for an investigational drug, pentamorphone, puissance d’une drogue expérimentale, le pentamorphone, compara- compared with morphine is reported. Pentamorphone was found to tivement à la morphine, est rapportée. On a mis en évidence que le pen- be more efficacious than morphine in the first hour after surgery tamorphone était plus efficace que la morphine dans la première heure because significantly more patients were able to achieve a visual qui suit la chirurgie parce que d’une manière significative, plus de pa- analogue scale of less than 30 mm with pentamorphone. Thereafter tients pouvaient compléter une échelle visuelle analogique de moins de pentamorphone and morphine were found to be equally effica- 30 mm avec le pentamorphone. Après, le pentamorphone et la mor- cious. Initially pentamorphone may be more potent than morphine phine démontraient une efficacité similaire. Initialement, le pentamor- based on the greater volume of morphine used in the first hour of phone pourrait être plus puissant que la morphine sur la base de la plus therapy. However, a potency ratio could not be determined be- grande quantité de morphine administrée au cours de la première heure cause this result was under conditions of unequal analgesia. The du traitement. Cependant un indexe de puissance n’a pu être défini potency ratio determined at 24 h of therapy under equianalgesic parce que ce résultat a été obtenu dans des conditions d’analgésie iné- conditions (252:1) is similar to previously reported potency data gale. L’indexe de puissance défini après 24 h de traitement dans des from laboratory studies (200:1). This study supports the use of conditions d’analgésie égale (252:1) est similaire à l’indexe de puis- PCA as a model to investigate and compare new drugs to establish sance rapporté auparavant dans les données provenant des études de their efficacy and potency. laboratoire (200:1). La présente étude appuie l’utilisation du CAP Key Words: Morphine, Patient controlled analgesia, Pentamor- comme modèle pour rechercher et comparer des nouveaux médica- phone, Postoperative ments afin d’établir leur efficacité et leur puissance. Department of Anesthesiology, Duke University Medical Center, Durham, North Carolina, USA Correspondence and reprints: Dr B Ginsberg, Department of Anesthesiology, Box 3094, Duke University Medical Center, Durham, North Carolina 27710, USA. Telephone 919-681-5396, fax 919-681-8994, e-mail [email protected] Accepted for publication June 12, 1996 PAIN RES MANAGE VOL 1 NO 4 WINTER 1996 227 Ginsberg et al atient controlled analgesia (PCA) is widely used for the man- TABLE 1 agement of postoperative pain and is highly effective in provid- P Demographics and total fentanyl used ing adequate pain relief (1,2). With appropriate choice of opioid Pentamorphone Morphine doses and lockout intervals, patients using PCA can obtain pain re- lief regardless of the specific pharmacodynamic and pharmacoki- Age (years) 49.5±12 49.17±8.7 netic properties of the opioids chosen (3-5). Thus PCA should be Height (cm) 165.5±8.2. 62.1±8.1 useful as a research tool to compare opioids (6,7). Efficacy can be Weight (kg) 72.9±14.2 74.3±14.5 studied through determination of the degree of pain relief obtained – Surgery (mins) 213±70.5 .211±68.3 using a visual analogue scale (VAS) – with each analgesic at vari- Intraoperative fentanyl (mg) 287.1±177 280.6±128.8 ous 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 us- ing PCA with a new drug, pentamorphone, versus morphine, after lower abdominal surgery. Pentamorphone (14-beta-n- pentylaminomorphinone) is a morphine derivative with a high lipo- philicity and fairly stable cardiovascular effects (8,9). In animal studies pentamorphone had a shorter onset and duration than mor- phine (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 Medi- cal Center, written informed consent was obtained from 60 patients scheduled to undergo lower abdominal surgery (exploratory lapa- rotomy, abdominal hysterectomy, oophorectomy, etc). Only American Society of Anesthesiologists physical status I or II pa- Figure 1) Bar graph representing visual analogue pain scale comparing pentamorphone with morphine. *P<0.05 tients 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. was repeated up to three times for a VAS greater than 50 mm while Patients underwent standardized education on the use of the Ab- in the PACU. If these loading doses provided inadequate analgesia, bott Lifecare PCA (Illinois). The pamphlet details that patients patients were excluded from the study and conventional analgesia should use the PCA expectantly and keep their pain level at a man- was started. PCA settings were standardized to a maintenance dose ageable, mild level was emphasized. In addition, education served of 0.02 mL/kg and a lockout interval of 8 mins. Patients were dis- to allay potential fears or social mores regarding the use of a PCA charged from the PACU to a routine postoperative floor when machine. As a part of the process, patients were instructed on how to awake with a satisfactory level of analgesia. A VAS (completed by complete a linear VAS (on a scale of 1 to 100). the patient), sedation scale and side effects (completed via observa- Patients were randomly assigned, in a double-blind fashion, to tion and open questions) were recorded at 10, 20 and 30 mins and at one of two groups. Twenty patients received morphine and the other 1, 4, 8, 12, 16, 20 and 24 h. 40 received pentamorphone for postoperative analgesia. The po- Analysis of variance for repeated measures was used for com- tency of pentamorphone has previously been determined in a labor- parison between the groups. The Mann Whitney U test was used for atory setting with human volunteers (9). The data from this study comparison of nonparametric data. P<0.05 was considered signifi- were used to derive the initial dosing for pentamorphone compared cant. Results are given as a mean ± SD. with morphine. Estimated equipotent doses of morphine (1 mg/mL) m and pentamorphone (5 g/mL) were prepared for the PCA pump by RESULTS the pharmacy. The two groups showed no differences in age, height or weight, du- Anesthesia was standardized to include thiopental, 60% to 70% ration of surgical procedure and total amount of intraoperative fen- m nitrous oxide and isoflurane supplemented with less than 6 g/kg tanyl used (Table 1). Initial VAS scores showed no statistical fentanyl as necessary to maintain adequate anesthesia. Vecuronium difference before the first loading dose of pentamorphone was used for neuromuscular blockade and was antagonized with (81±18 mm) or morphine (83±18 mm). The VAS following the ini- neostigmine and glycopyrrolate at the end of the procedure. tial loading dose of pentamorphone (51±31 mm) and morphine In the postanesthesia care unit (PACU) a loading dose of (63±32 mm) showed no statistical difference. However, the VAS 0.04 mL/kg of the randomized analgesic was administered via an was significantly lower at 20, 30 and 60 mins in the pentamorphone m Abbott Lifecare PCA. This translated into either 40 g/kg morphine group compared with the morphine group (P<0.05) (Figure 1). The m or 0.2 g/kg pentamorphone. This loading dose of opioid was given percentage of patients who received pentamorphone with a VAS when a VAS greater than 50 mm was recorded by the patient, and less than 30 mm was significantly greater than the percentage of 228 PAIN RES MANAGE VOL 1 NO 4 WINTER 1996 PCA as a tool to assess a new opioid 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 de- picted in Figure 3. During the initial period, patients in the penta- morphone 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 vol- umes of opioid.