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The History of Patient-Controlled Analgesia
BULLETIN OF
EST ESIA J-lIST
RY APRIL, 1998
VOLUME 16, NUMBER 2
The History of Patient-Controlled Analgesia by Ricardo Sepulveda, M.D. Resident in Anesthesiology, University of Florida College oflvledicine Entry for Anesthesia Hist01Y Association Resident's Essay Contest, 1997 Advances in the neurophysiology and neu rochemistry of pain have given researchers the opportunity to explore more effective methods to treat postoperative pain. An in creased concern among caregivers regarding inadequate pain relief, and the development of patient controlled analgesia (PCA) systems has led to intensified research and a better understanding of pain management. The developments in PCA technology and other pain control techniques have given physicians the oPlJortunity to choose from various agents, dosages and strategies for pain management in the hospital and outpatient settings. Morphine continues to be the standard to which all analgesics are compared. The un bound, unionized, and lipophilic character istics of opioids make them free to cross mem branes and gain access to the mu, delta, kappa, epsilon and sigma receptors. These
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opioid receptors have preferences for particu lar stereochemical configurations. The com bination of receptor preferences, stereochemi cal variability, and cross reactions arnong re ceptors account for the spectrum of clinical effects. Specific effects of stimulating the mu receptor, for example, include analgesia, ven tilatory depression, euphoria, decreased gut peristalsis, and opioid dependence. The con centration of agonist at the mu receptors within the brain and spinal cord dictate the degree of stimulation; the mechanism is not an all-or-none phenomenon. A specific drug concentration may provide adequate analge sia to one patient and cause apnea in another. Pain is defined as "a sensory and emo tional experience associated with actual or potential tissue damage or which is described in terms of such damage".1 Postoperative pain usually comprises a relatively constant pain
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CONCENTRATION (&101m!) Figure 1. The relation between plasma concentration of opioid and analgesia. For a minimal increase in opioid concentration above the maximum concentration still associated with severe pain (Mep) (first inflection point), there is a rapid and dramatic decrease in pain. TIle nadir of the perceivedpain (second inflection point) is called the minimum effective analgesic concentration (ivIEAe). TIle slope of the line between Mep and MEAe is steep, with as little as 0.05 pg/ml of meperidine making the difference between severe pain and analgesia. (From: Austin KH, Stapletoll Jl? iHather LE. Relationship between blood meperidine concentrations and analgesic response: a preliminary report. Anesthesiology 53:460-466, 1 980.)
that may vary in intensity over time, along with acute pain exacerbations associated with specific incidents that are superimposed on the constant pain. The specific incident may include coughing and deep breathing exercises, dressing changes and patient movement. In the early 1970s, Marks and Sachar re ported that patients received only 25% of the intramuscular (1M) medication ordered by physicians on an "as needed" basis for their postoperative pain.2 The gold standard for postoperative analgesia had been morphine, 10 mg 1M, every 3-4 hr. However, further stud ies confirmed that this dosage resulted in up to 70% of .patients reporting significant amounts of unrelieved pain.3,4 By the time nursing staff evaluates a patient's pain, ac quires the analgesic medication, and admin isters the proper dose, the patient can suffer from inadequate pain relief for a significant period of time.s Alarmingly, almost 20 years after the Marks and Sachar study, and with the advances in PCA, patients were still pre scribed 1M analgesic medications and con tinued to suffer significant unrelieved pain until the late 1980s, when PCA devices fi nally gained widespread acceptance. In 1980 the concentration-effect curve was used to describe the narrow range of opioid concentration that separated severe pain from adequate analgesia.6 Within the therapeutic window, an increase as low as 0.05 Ilg/ml of meperidine, above an analgesic concentration associated with severe pain, led to a dramatic decrease in pain (Figure 1). This concept be came known as the minimum effective anal gesic concentration (MEAC). In the 1980 study by Austin et al./ the MEAC was not achieved in 60% of the patients who received 100 mg of meperidine. Austin et al. 6 and oth ers7,8 confirmed that the MEAC typically varied among individuals. If an individual's plasma concentration was consistently mainContinued 01/ Page 4
4
peA .
BULLETIN OF ANESTHESIA HISTORY
. . COlllillued from Page 1
tained above the MEAC, adequate analgesia was reported.9,lo Therefore, for PCA to be therapeutic, a stable relationship must exist between plasma concentration, analgesic ef fect, and proper dosing intervals5 (Figure 2). In separate studies, Ferrante et aU and Whitell demonstrated that intravenous PCA provided more stable serum levels of analge sic medication thanIM injection. Even sched uled 1M injections resulted in unpredictable plasma concentrations because the opioids were absorbed from the muscular site at an unpredictable rate. With intravenous PCA, patients self-administered their opioid dos ages in small increments to maintain plasma levels around their individual MEAC, with out the risk of overdose, because a sedated patient was unable to administer more opioid. Patients receiving intravenous PCA required less opioid than those who received 1M opioids to achieve pain control when pain was measured by the visual linear analogue pain scale.5,12 Also, patients who received intravenous PCA had an overall decrease in the incidence of respiratory depression and reported less pain when compared to those who received 1M narcotics on an "as needed" basis. Because opioid requirements varied among patients, investigators looked for in dividual patient characteristics that might influence these variations. Bellville13 and Burns et al.14 reported decreased analgesic demands and increased pain relief among elderly compared to younger patients. Based on the principles of pharmacokinetics, the characteristic decreased volume of distribu tion and decreased opioid clearance rates in the elderly population accounted for in creased serum concentrations. Therefore, eld erly patients should have decreased opioid requirements. It is also possible that elderly people have greater binding affinities, changes in the number of opioid receptors, or increased sensitivities to certain drug con centrations. Other factors that contributed to the variability of analgesic levels among in dividuals included a low threshold for pain tolerance (i.e., cultural tradition, traumatic experiences), or previous histOlY of anxiety. Early studies of psychologic factors that in fluenced 1M opioid requirements revealed a definite relation among anxiety, neuroticism, and pain tolerance.l5,l6 Fear and confusion may further exacerbate an individual's anal gesic variability. Several studies that com pared the opioid requirements of men and women revealed that men requested more medication than women.8,14,17,18 Other stud ies, however, did not observe such differ ences.3,19 Other factors, such as body surface area and weight were not reported to signifi cantly influence PCA use.9
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Figure 2. TIle peA Paradigm. TIze relation among plasma opioid concentration (ordinate), dosing interval (abscissa), and analgesic effect (z axis) defining therapeutic effectiveness. (From: Ferrante FM, Orav EJ, Rocco A G, Gallo J: A statistical model for pain ill patient-controlred analgesia and cOllventional intramuscular opioid regimens. Anesth Analg 67: 457-461, 1 988.) Research continued to focus on the phar macologic factors in patient-demand analge sia. Investigators studied the pharmacokinet ics of meperidine, ketobemidone and mor phine in an attempt to explain the wide vari ability in analgesic requirements. The volume of distribution, rate of distribution and rate of elimination did not correlate with an individual's dose requirements.9,2o One study examined 40 postoperative patients using meperidine for PCA and found that the dose ranged from 12-100 mg/hr.21 Some patients required low dosages and were comfortable, even after upper abdominal surgery, whereas others experienced comparatively little pain relief with high analgesic dosages after mi nor surgery. Investigators then hypothesized that changes in the endogenous opioid levels or changes in receptor number or affinity might account for individual analgesic re quirements. In 1982, Tamsen et al. reported that the MEAC was directly influenced by the level of preoperative endogenous opioid concentrations in the cerebral spinal fluid. 22 Patients who had low preoperative endog enous opioid levels in the cerebral spinal fluid required more analgesics postoperatively to maintain higher drug levels in the plasma. Therefore, each patient titrated his opioid dosage to that level necessalY to supplement endogenous opioids for pain relief in the post operative period. PCA has also been used as a tool to study the potency, efficacy and duration of various opioids. 23 PCA successfully eliminated ex perimenter bias by placing the patient in con trol of opioid requirements to maintain opti mal pain relief. One drawback of PCA was that some patients did not use the PCA de vice to achieve "complete" pain relief, but rather tolerated some pain due to uncomfort able side effects or unexplained psychologi cal traits. Despite these influences, the aver age consumption and efficacy of individual
drugs remained consistent.5 The next stage of research involved the determination of equianalgesic ratios between different routes of PCA administration. Estok et al.24 com pared pain relief between epidural and in travenous fentanyl, and revealed that ad equate analgesia was dependent on plasma opioid levels, regardless of the method used. When PCA devices were configured to deliver an exact dosage, knowledge of the pharmacologic and therapeutic windows of the opioid were essential. Although therapeu tic indices were acquired in experimental conditions, postoperative PCA infusion doses were tailored to the analgesic plasma level required by each individual. Frequently, a priming dose of opioid was delivered, which was then increased stepwise until sufficient pain relief was obtained. This technique used the P CA primarily to maintain analgesia rather than to establish it. With each injec tion, the patient received an analgesic effect just above the MEAC. If this dose was too small, the patient increased the dosage fre quency. Studies revealed that patients had an inherent maximum demand frequency in which they either refrained from making de mands or just gave up on the system alto gether.25 If a suitable demand dose was al tered during PCA, patients modified the fre quency to maintain a consistent plasma opioid leveJ. 26 Another addition to PCA was the lockout interval, which prevented over dosage. Most modern PCA devices now re strict the lockout time to a minimum of five minutes, which should be long enough for patients to achieve the maximal analgesic effect from the previous dose before another is permitted. Overall, optimum settings of opioid administration result in achieving a high therapeutic index, which is the goal of pharmacological therapy. In the late 1960s, intravenous demand analgesia was achieved by a nurse continu-
BULLETIN OF ANESTHESIA HISTORY
ously at the patient's bedside delivering small intravenous opioid boluses when requested.27 By the mid-1970s, the Cardiff Palliator was developed and commercially available for PCA administration.28 With the sensation of pain, the patient activated the syringe pump system by pressing a button to sequentially dispense an opioid bolus dose. After the bo lus infusion, the next demand was fulfilled at the end of a programmed lockout time. Further advances resulted in more PCA de vices and constant maintenance infusion sys tems with supplemental demand doses. In 1985, another PCA device, the On-Demand Analgesia Computer, allowed bolus demand doses and a baseline continuous infusion at an adaptive or fixed rate.29 When the adap tive rate was used, the actual infusion was calculated from the doses administered dur ing the previous 60-minute interval so that, if there had been a high demand, the baseline rate would be increased accordingly. In the fixed rate mode, the baseline infusion was programmed by the physician to maintain analgesia for each patient. In 1991, a PCA system was developed for the purpose of long-term pain control.l° This system pro vided a steady-state opioid infusion and al lowed patients to regulate the plasma opioid concentration by using a computer-controlled infusion pump, which accepted individual pharmacokinetic parameters. The pharmacokinetically-based patient control analgesic system was able to provide stable plasma concentrations and avoid the fluctua tions in concentration and drug effect inher ent in bolus dose approaches.30 Another adaptation of PCA technology includes the epidural administrat,ion of an algesics to produce prolonged segmental an esthesia. The discovery of spinal opiate re ceptors in 1976 fostered intensive research into the intrathecal and epidural administra tion of opioids.31,32 In 1988, Gambling and his associates compared patient controlled epi dural anesthesia (PCEA) with continuous infusion epidural analgesia using 0.125% bupivacaine.33 They reported excellent anal gesia, minimal motor blockade, and similar sensory levels with both PCEA and continu ous infusion methods. However, less anes thetic was used by the PCEA group. When comparing the two methods, the PCEA regi men carried the potential risk for an intra vascular or subarachnoid injection of anes thetic due to catheter migration. Today, the combination of continuous opioid infusions and local anesthetics allow a synergistic ef fect and aids patient comfort while awaiting the analgesic effect of the epidural narcotic. Because of patient variability, it is impos sible to accurately predict how much pain a patient will suffer postoperatively or the an algesic dose necessary to ablate the majority
of it. The influence of psychological variables on pain behavior continue to make the stan dardization of PCA difficult. However, with PCA the patient is given the opportunity to select the drug concentration that provides the best analgesia with minimal side effects. Advances in continuous infusion-based PCA, and other techniques of pain management, have allowed patients to adequately control postoperative pain and has given physicians a better understanding of . the pharmacodynamics of pain. With the continued progress in micropro cessor technology, PCA devices have been developed ''lith expanded memory and the capability to accurately deliver different opio ids of various potencies. Today's PCA devices have improved microprocessors for extensive memory storage, including time of dose de livery, pump settings, etc., alarms, and even miniaturization. By sacrificing memory for portability and simplicity, a number of min iature pumps are available that offer long-term PCA to ambulatOlY patients. Over all, there are a wide variety of PCA devices with special features to accommodate the majority of patient conditions. References 1. Merskey H, Albe-Fessard DG, Bonica JJ, et al. Pain terms: A list with definitions and notes on us age. Pain 6: 249-252,1979. 2. Marks RM, Sachar EL. Undertreatment of medical inpatients with narcotic analgesics. Ann In tel'll Med 78: 173- 1 8 1 ,1 973. 3. Keeri-Szanto M, Heaman .S. Postoperative demand analgesia. Swg Gynecol Obstet 134: 647-651 , 1972. 4. Donovan BD. Patient attitudes to postopera tive pain relief. Anaesth Intensive Care 1 1 : 125-129, 1983. 5. Ferrante FM, Orav EJ, Rocco AG, Gallo ]. A statistical model for pain in patient-controlled anal gesia and conventional intramuscular opioid regi mens. Anesth Analg 67: 457-461 ,1988. 6. Austin KL, Stapleton Jv, Mather LE. Relation ship between blood meperidine concentrations and analgesic response: A preliminary report. Anesthesi ology 53: 460-466,1980. 7. Keeri-Szanto M. The kinetics of postoperative analgesia. Clin Pham/acol T7ter 27: 263,1980. 8. Gourlay GK, Kowalski SR, PlummerJL, Cous ins MJ, Armstrong PL. Fentanyl b l o o d concentration-analgesic response relationship i n the treatment of postoperative pain. Anesth Analg 67: 329-337, 1988. 9. Tamsen A, Hartvig P, Fagerlund C, Wahlstrom B. Patient-controlled analgesic therapy, Part II: Indi vidual analgesic demand and analgesic plasma con centrations of pethidine in postoperative pain. Clin Pharmacokinet 7: 164-175, 1982. 10. Austin KL, Stapleton Jv, Mather LE. Mul tiple intramuscular injections: a major source ofvari ability in analgesic response to meperidine. Pain 8: 47-62, 1980. 11. White PF. Patient-controlled analgesia: A new approach to the management of postoperative pain. Sell/in Anesth 4: 255-266,1985. 1 2. Bennett RL, B a tenhorst RL, Foster TS, Griffen WO, Wright BD. Postoperative pulmonary function with patient-controlled analgesia, abstract. Anesth Analg 61: 171,1982. 13. Bellville J\V; Forrest WH Jl; Miller E, Brown BW Jr. Influence of age on pain relief from analge sics. A study of postoperative patients. JAMA 2 1 7:
1835-1841, 1971. 14. Burns J\V; Hodsman NB, McLintock TT, Gillies G\V; Kenny GN, McArdle CS. The influence of patient characteristics on the requirements for postoperative analgesia. A reassessment using patient-controlled analgesia.Anaesthesia44: 2-6,1989. 15. Martinez-Urutia A. Anxiety and pain in sur gical patients.] Consult Clin Hy cl101 43: 437-442,1 975. 16. Cronin M, Redfern PA, Utting JE. Psychia try and postoperative complaints in surgical patients. BrJ Anaesth 45: 879-886, 1973. 17. Bullingham RE, McQuay HJ, Dwyer D, Allen MC, Moore RA. Sublingual buprenorphine used post operatively: clinical observations and preliminary pharmacokinetic analysis. Br J Clin Pharmacol 12: 1 1 7-122, 1981. 18. Watson PJ, McQuay HJ, Bullingham RES, Allen MC, Moore RA. Single-dose comparison of buprenorphine OJ and 0.6 mg i.v. given after opera tion: clinical effects and plasma concentration. Br J Anaesth 54: 37-43,1982. 19. Bennett RL, Batenhorst R, Graves DA, Fos ter TS, Baumann T, Griffen WO, Wright BD. Varia tion in postoperative analgesic requirements in the morbidly obese following gastric bypass surgely. Phmc macotherapy 2: 50-53, 1982. 20. Dahlstrom B, Tamsen A, Paalzow L, Hartvig P. Patient-controlled analgesic therap)\ Part IV: Phar macokinetics and analgesic plasma concentrations of morphine. Clin Pharmacokinetics 7: 266-279,1982. 21. Lehmann KA. Patient-controlled intravenous analgesia for postoperative pain . relief. Adv Pain Res Ther 1 8: 481-506,1991. 22. Tamsen A, S a k u rada T, D ahlstrom A , Terenius L , Hartvig P. Postoperative demand for an algesics in relation to individual levels of endorphins and substance P in cerebrospinal fluid. Pain 13: 1 7 1 - 1 83,1982. 23. Mather LE. Pharmacokinetic and pharma codynamic factors influencing the choice, dose and route of administration of opiates for acute pain, in Bullingham RES (ed): OpiateAnalgesia. London, \'I1B Saunders, 1983,pp 1 7-40. 24. Estok PM, G l ass PSA, Goldberg J S , Freilberger JJ, Sladen RN. Use o f patient controlled analgesia to compare intravenous to epidural admin istration of fentanyl. in the postoperative patient.An esthesiology 67: A230,1987. 25. Owen H, Plummer JL, Armstrong I, Mather LE, Cousins M]. Variables of patient controlled an algesia. 1. Bolus size. Anaesthesia 44: 7-10, 1989. 26. Lehmann KA, Heinrich C, van Heiss R. Bal anced anesthesia and patient-controlled postopera tive analgesia with fentanyl: minimum effective con centrations, accumulation and acute tolerance. Acta Anaesthesiol Belg 39: 1 1 -23,1988. 27. Sechzer P. Objective measurement of pain. Anesthesiology 29: 209-2 10, 1968. 28. Evans JM, Rosen 11'1, McCarthy J, Rosen M, Hogg MI. Apparatus for patient-controlled adminis tration of intravenous narcotics during labour. Lan cet 1: 17-18,1976. 29. Hull CJ. An on-demand analgesia computer. In: Harmer M, Rosen M, VIckers MD, eds. Patielll Controlled Analgesia. Oxford: B lackwell Scientific Publications, 1985,pp 83-86. 30. H i l l HF, Mackie AM, Coda BA. Patient-controlled analgesic infusion. Adv Pain Res TIleI' 1 8: 507-523, 1991. 31. Yaksh TL, Rudy TA. Analgesia mediated by a direct spinal action of narcotics. Science 1 92; 1357-1358, 1976. 32. Cousins MJ, Mather LE. Intrathecal and epi dural administration of opioids. Anesthesiology 6 1 : 276-310, 1984. 33. Gambling DR, Yu P, Cole C, McMorland GH, Palmer L. A comparative study of patient controlled epidural analgesia (PCEA) and continuous infusion epidural analgesia (CIEA) during labour. Can J Anaesth 35: 249-254, 1988.
EST ESIA J-lIST
RY APRIL, 1998
VOLUME 16, NUMBER 2
The History of Patient-Controlled Analgesia by Ricardo Sepulveda, M.D. Resident in Anesthesiology, University of Florida College oflvledicine Entry for Anesthesia Hist01Y Association Resident's Essay Contest, 1997 Advances in the neurophysiology and neu rochemistry of pain have given researchers the opportunity to explore more effective methods to treat postoperative pain. An in creased concern among caregivers regarding inadequate pain relief, and the development of patient controlled analgesia (PCA) systems has led to intensified research and a better understanding of pain management. The developments in PCA technology and other pain control techniques have given physicians the oPlJortunity to choose from various agents, dosages and strategies for pain management in the hospital and outpatient settings. Morphine continues to be the standard to which all analgesics are compared. The un bound, unionized, and lipophilic character istics of opioids make them free to cross mem branes and gain access to the mu, delta, kappa, epsilon and sigma receptors. These
MCP "
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opioid receptors have preferences for particu lar stereochemical configurations. The com bination of receptor preferences, stereochemi cal variability, and cross reactions arnong re ceptors account for the spectrum of clinical effects. Specific effects of stimulating the mu receptor, for example, include analgesia, ven tilatory depression, euphoria, decreased gut peristalsis, and opioid dependence. The con centration of agonist at the mu receptors within the brain and spinal cord dictate the degree of stimulation; the mechanism is not an all-or-none phenomenon. A specific drug concentration may provide adequate analge sia to one patient and cause apnea in another. Pain is defined as "a sensory and emo tional experience associated with actual or potential tissue damage or which is described in terms of such damage".1 Postoperative pain usually comprises a relatively constant pain
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CONCENTRATION (&101m!) Figure 1. The relation between plasma concentration of opioid and analgesia. For a minimal increase in opioid concentration above the maximum concentration still associated with severe pain (Mep) (first inflection point), there is a rapid and dramatic decrease in pain. TIle nadir of the perceivedpain (second inflection point) is called the minimum effective analgesic concentration (ivIEAe). TIle slope of the line between Mep and MEAe is steep, with as little as 0.05 pg/ml of meperidine making the difference between severe pain and analgesia. (From: Austin KH, Stapletoll Jl? iHather LE. Relationship between blood meperidine concentrations and analgesic response: a preliminary report. Anesthesiology 53:460-466, 1 980.)
that may vary in intensity over time, along with acute pain exacerbations associated with specific incidents that are superimposed on the constant pain. The specific incident may include coughing and deep breathing exercises, dressing changes and patient movement. In the early 1970s, Marks and Sachar re ported that patients received only 25% of the intramuscular (1M) medication ordered by physicians on an "as needed" basis for their postoperative pain.2 The gold standard for postoperative analgesia had been morphine, 10 mg 1M, every 3-4 hr. However, further stud ies confirmed that this dosage resulted in up to 70% of .patients reporting significant amounts of unrelieved pain.3,4 By the time nursing staff evaluates a patient's pain, ac quires the analgesic medication, and admin isters the proper dose, the patient can suffer from inadequate pain relief for a significant period of time.s Alarmingly, almost 20 years after the Marks and Sachar study, and with the advances in PCA, patients were still pre scribed 1M analgesic medications and con tinued to suffer significant unrelieved pain until the late 1980s, when PCA devices fi nally gained widespread acceptance. In 1980 the concentration-effect curve was used to describe the narrow range of opioid concentration that separated severe pain from adequate analgesia.6 Within the therapeutic window, an increase as low as 0.05 Ilg/ml of meperidine, above an analgesic concentration associated with severe pain, led to a dramatic decrease in pain (Figure 1). This concept be came known as the minimum effective anal gesic concentration (MEAC). In the 1980 study by Austin et al./ the MEAC was not achieved in 60% of the patients who received 100 mg of meperidine. Austin et al. 6 and oth ers7,8 confirmed that the MEAC typically varied among individuals. If an individual's plasma concentration was consistently mainContinued 01/ Page 4
4
peA .
BULLETIN OF ANESTHESIA HISTORY
. . COlllillued from Page 1
tained above the MEAC, adequate analgesia was reported.9,lo Therefore, for PCA to be therapeutic, a stable relationship must exist between plasma concentration, analgesic ef fect, and proper dosing intervals5 (Figure 2). In separate studies, Ferrante et aU and Whitell demonstrated that intravenous PCA provided more stable serum levels of analge sic medication thanIM injection. Even sched uled 1M injections resulted in unpredictable plasma concentrations because the opioids were absorbed from the muscular site at an unpredictable rate. With intravenous PCA, patients self-administered their opioid dos ages in small increments to maintain plasma levels around their individual MEAC, with out the risk of overdose, because a sedated patient was unable to administer more opioid. Patients receiving intravenous PCA required less opioid than those who received 1M opioids to achieve pain control when pain was measured by the visual linear analogue pain scale.5,12 Also, patients who received intravenous PCA had an overall decrease in the incidence of respiratory depression and reported less pain when compared to those who received 1M narcotics on an "as needed" basis. Because opioid requirements varied among patients, investigators looked for in dividual patient characteristics that might influence these variations. Bellville13 and Burns et al.14 reported decreased analgesic demands and increased pain relief among elderly compared to younger patients. Based on the principles of pharmacokinetics, the characteristic decreased volume of distribu tion and decreased opioid clearance rates in the elderly population accounted for in creased serum concentrations. Therefore, eld erly patients should have decreased opioid requirements. It is also possible that elderly people have greater binding affinities, changes in the number of opioid receptors, or increased sensitivities to certain drug con centrations. Other factors that contributed to the variability of analgesic levels among in dividuals included a low threshold for pain tolerance (i.e., cultural tradition, traumatic experiences), or previous histOlY of anxiety. Early studies of psychologic factors that in fluenced 1M opioid requirements revealed a definite relation among anxiety, neuroticism, and pain tolerance.l5,l6 Fear and confusion may further exacerbate an individual's anal gesic variability. Several studies that com pared the opioid requirements of men and women revealed that men requested more medication than women.8,14,17,18 Other stud ies, however, did not observe such differ ences.3,19 Other factors, such as body surface area and weight were not reported to signifi cantly influence PCA use.9
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Figure 2. TIle peA Paradigm. TIze relation among plasma opioid concentration (ordinate), dosing interval (abscissa), and analgesic effect (z axis) defining therapeutic effectiveness. (From: Ferrante FM, Orav EJ, Rocco A G, Gallo J: A statistical model for pain ill patient-controlred analgesia and cOllventional intramuscular opioid regimens. Anesth Analg 67: 457-461, 1 988.) Research continued to focus on the phar macologic factors in patient-demand analge sia. Investigators studied the pharmacokinet ics of meperidine, ketobemidone and mor phine in an attempt to explain the wide vari ability in analgesic requirements. The volume of distribution, rate of distribution and rate of elimination did not correlate with an individual's dose requirements.9,2o One study examined 40 postoperative patients using meperidine for PCA and found that the dose ranged from 12-100 mg/hr.21 Some patients required low dosages and were comfortable, even after upper abdominal surgery, whereas others experienced comparatively little pain relief with high analgesic dosages after mi nor surgery. Investigators then hypothesized that changes in the endogenous opioid levels or changes in receptor number or affinity might account for individual analgesic re quirements. In 1982, Tamsen et al. reported that the MEAC was directly influenced by the level of preoperative endogenous opioid concentrations in the cerebral spinal fluid. 22 Patients who had low preoperative endog enous opioid levels in the cerebral spinal fluid required more analgesics postoperatively to maintain higher drug levels in the plasma. Therefore, each patient titrated his opioid dosage to that level necessalY to supplement endogenous opioids for pain relief in the post operative period. PCA has also been used as a tool to study the potency, efficacy and duration of various opioids. 23 PCA successfully eliminated ex perimenter bias by placing the patient in con trol of opioid requirements to maintain opti mal pain relief. One drawback of PCA was that some patients did not use the PCA de vice to achieve "complete" pain relief, but rather tolerated some pain due to uncomfort able side effects or unexplained psychologi cal traits. Despite these influences, the aver age consumption and efficacy of individual
drugs remained consistent.5 The next stage of research involved the determination of equianalgesic ratios between different routes of PCA administration. Estok et al.24 com pared pain relief between epidural and in travenous fentanyl, and revealed that ad equate analgesia was dependent on plasma opioid levels, regardless of the method used. When PCA devices were configured to deliver an exact dosage, knowledge of the pharmacologic and therapeutic windows of the opioid were essential. Although therapeu tic indices were acquired in experimental conditions, postoperative PCA infusion doses were tailored to the analgesic plasma level required by each individual. Frequently, a priming dose of opioid was delivered, which was then increased stepwise until sufficient pain relief was obtained. This technique used the P CA primarily to maintain analgesia rather than to establish it. With each injec tion, the patient received an analgesic effect just above the MEAC. If this dose was too small, the patient increased the dosage fre quency. Studies revealed that patients had an inherent maximum demand frequency in which they either refrained from making de mands or just gave up on the system alto gether.25 If a suitable demand dose was al tered during PCA, patients modified the fre quency to maintain a consistent plasma opioid leveJ. 26 Another addition to PCA was the lockout interval, which prevented over dosage. Most modern PCA devices now re strict the lockout time to a minimum of five minutes, which should be long enough for patients to achieve the maximal analgesic effect from the previous dose before another is permitted. Overall, optimum settings of opioid administration result in achieving a high therapeutic index, which is the goal of pharmacological therapy. In the late 1960s, intravenous demand analgesia was achieved by a nurse continu-
BULLETIN OF ANESTHESIA HISTORY
ously at the patient's bedside delivering small intravenous opioid boluses when requested.27 By the mid-1970s, the Cardiff Palliator was developed and commercially available for PCA administration.28 With the sensation of pain, the patient activated the syringe pump system by pressing a button to sequentially dispense an opioid bolus dose. After the bo lus infusion, the next demand was fulfilled at the end of a programmed lockout time. Further advances resulted in more PCA de vices and constant maintenance infusion sys tems with supplemental demand doses. In 1985, another PCA device, the On-Demand Analgesia Computer, allowed bolus demand doses and a baseline continuous infusion at an adaptive or fixed rate.29 When the adap tive rate was used, the actual infusion was calculated from the doses administered dur ing the previous 60-minute interval so that, if there had been a high demand, the baseline rate would be increased accordingly. In the fixed rate mode, the baseline infusion was programmed by the physician to maintain analgesia for each patient. In 1991, a PCA system was developed for the purpose of long-term pain control.l° This system pro vided a steady-state opioid infusion and al lowed patients to regulate the plasma opioid concentration by using a computer-controlled infusion pump, which accepted individual pharmacokinetic parameters. The pharmacokinetically-based patient control analgesic system was able to provide stable plasma concentrations and avoid the fluctua tions in concentration and drug effect inher ent in bolus dose approaches.30 Another adaptation of PCA technology includes the epidural administrat,ion of an algesics to produce prolonged segmental an esthesia. The discovery of spinal opiate re ceptors in 1976 fostered intensive research into the intrathecal and epidural administra tion of opioids.31,32 In 1988, Gambling and his associates compared patient controlled epi dural anesthesia (PCEA) with continuous infusion epidural analgesia using 0.125% bupivacaine.33 They reported excellent anal gesia, minimal motor blockade, and similar sensory levels with both PCEA and continu ous infusion methods. However, less anes thetic was used by the PCEA group. When comparing the two methods, the PCEA regi men carried the potential risk for an intra vascular or subarachnoid injection of anes thetic due to catheter migration. Today, the combination of continuous opioid infusions and local anesthetics allow a synergistic ef fect and aids patient comfort while awaiting the analgesic effect of the epidural narcotic. Because of patient variability, it is impos sible to accurately predict how much pain a patient will suffer postoperatively or the an algesic dose necessary to ablate the majority
of it. The influence of psychological variables on pain behavior continue to make the stan dardization of PCA difficult. However, with PCA the patient is given the opportunity to select the drug concentration that provides the best analgesia with minimal side effects. Advances in continuous infusion-based PCA, and other techniques of pain management, have allowed patients to adequately control postoperative pain and has given physicians a better understanding of . the pharmacodynamics of pain. With the continued progress in micropro cessor technology, PCA devices have been developed ''lith expanded memory and the capability to accurately deliver different opio ids of various potencies. Today's PCA devices have improved microprocessors for extensive memory storage, including time of dose de livery, pump settings, etc., alarms, and even miniaturization. By sacrificing memory for portability and simplicity, a number of min iature pumps are available that offer long-term PCA to ambulatOlY patients. Over all, there are a wide variety of PCA devices with special features to accommodate the majority of patient conditions. References 1. Merskey H, Albe-Fessard DG, Bonica JJ, et al. Pain terms: A list with definitions and notes on us age. Pain 6: 249-252,1979. 2. Marks RM, Sachar EL. Undertreatment of medical inpatients with narcotic analgesics. Ann In tel'll Med 78: 173- 1 8 1 ,1 973. 3. Keeri-Szanto M, Heaman .S. Postoperative demand analgesia. Swg Gynecol Obstet 134: 647-651 , 1972. 4. Donovan BD. Patient attitudes to postopera tive pain relief. Anaesth Intensive Care 1 1 : 125-129, 1983. 5. Ferrante FM, Orav EJ, Rocco AG, Gallo ]. A statistical model for pain in patient-controlled anal gesia and conventional intramuscular opioid regi mens. Anesth Analg 67: 457-461 ,1988. 6. Austin KL, Stapleton Jv, Mather LE. Relation ship between blood meperidine concentrations and analgesic response: A preliminary report. Anesthesi ology 53: 460-466,1980. 7. Keeri-Szanto M. The kinetics of postoperative analgesia. Clin Pham/acol T7ter 27: 263,1980. 8. Gourlay GK, Kowalski SR, PlummerJL, Cous ins MJ, Armstrong PL. Fentanyl b l o o d concentration-analgesic response relationship i n the treatment of postoperative pain. Anesth Analg 67: 329-337, 1988. 9. Tamsen A, Hartvig P, Fagerlund C, Wahlstrom B. Patient-controlled analgesic therapy, Part II: Indi vidual analgesic demand and analgesic plasma con centrations of pethidine in postoperative pain. Clin Pharmacokinet 7: 164-175, 1982. 10. Austin KL, Stapleton Jv, Mather LE. Mul tiple intramuscular injections: a major source ofvari ability in analgesic response to meperidine. Pain 8: 47-62, 1980. 11. White PF. Patient-controlled analgesia: A new approach to the management of postoperative pain. Sell/in Anesth 4: 255-266,1985. 1 2. Bennett RL, B a tenhorst RL, Foster TS, Griffen WO, Wright BD. Postoperative pulmonary function with patient-controlled analgesia, abstract. Anesth Analg 61: 171,1982. 13. Bellville J\V; Forrest WH Jl; Miller E, Brown BW Jr. Influence of age on pain relief from analge sics. A study of postoperative patients. JAMA 2 1 7:
1835-1841, 1971. 14. Burns J\V; Hodsman NB, McLintock TT, Gillies G\V; Kenny GN, McArdle CS. The influence of patient characteristics on the requirements for postoperative analgesia. A reassessment using patient-controlled analgesia.Anaesthesia44: 2-6,1989. 15. Martinez-Urutia A. Anxiety and pain in sur gical patients.] Consult Clin Hy cl101 43: 437-442,1 975. 16. Cronin M, Redfern PA, Utting JE. Psychia try and postoperative complaints in surgical patients. BrJ Anaesth 45: 879-886, 1973. 17. Bullingham RE, McQuay HJ, Dwyer D, Allen MC, Moore RA. Sublingual buprenorphine used post operatively: clinical observations and preliminary pharmacokinetic analysis. Br J Clin Pharmacol 12: 1 1 7-122, 1981. 18. Watson PJ, McQuay HJ, Bullingham RES, Allen MC, Moore RA. Single-dose comparison of buprenorphine OJ and 0.6 mg i.v. given after opera tion: clinical effects and plasma concentration. Br J Anaesth 54: 37-43,1982. 19. Bennett RL, Batenhorst R, Graves DA, Fos ter TS, Baumann T, Griffen WO, Wright BD. Varia tion in postoperative analgesic requirements in the morbidly obese following gastric bypass surgely. Phmc macotherapy 2: 50-53, 1982. 20. Dahlstrom B, Tamsen A, Paalzow L, Hartvig P. Patient-controlled analgesic therap)\ Part IV: Phar macokinetics and analgesic plasma concentrations of morphine. Clin Pharmacokinetics 7: 266-279,1982. 21. Lehmann KA. Patient-controlled intravenous analgesia for postoperative pain . relief. Adv Pain Res Ther 1 8: 481-506,1991. 22. Tamsen A, S a k u rada T, D ahlstrom A , Terenius L , Hartvig P. Postoperative demand for an algesics in relation to individual levels of endorphins and substance P in cerebrospinal fluid. Pain 13: 1 7 1 - 1 83,1982. 23. Mather LE. Pharmacokinetic and pharma codynamic factors influencing the choice, dose and route of administration of opiates for acute pain, in Bullingham RES (ed): OpiateAnalgesia. London, \'I1B Saunders, 1983,pp 1 7-40. 24. Estok PM, G l ass PSA, Goldberg J S , Freilberger JJ, Sladen RN. Use o f patient controlled analgesia to compare intravenous to epidural admin istration of fentanyl. in the postoperative patient.An esthesiology 67: A230,1987. 25. Owen H, Plummer JL, Armstrong I, Mather LE, Cousins M]. Variables of patient controlled an algesia. 1. Bolus size. Anaesthesia 44: 7-10, 1989. 26. Lehmann KA, Heinrich C, van Heiss R. Bal anced anesthesia and patient-controlled postopera tive analgesia with fentanyl: minimum effective con centrations, accumulation and acute tolerance. Acta Anaesthesiol Belg 39: 1 1 -23,1988. 27. Sechzer P. Objective measurement of pain. Anesthesiology 29: 209-2 10, 1968. 28. Evans JM, Rosen 11'1, McCarthy J, Rosen M, Hogg MI. Apparatus for patient-controlled adminis tration of intravenous narcotics during labour. Lan cet 1: 17-18,1976. 29. Hull CJ. An on-demand analgesia computer. In: Harmer M, Rosen M, VIckers MD, eds. Patielll Controlled Analgesia. Oxford: B lackwell Scientific Publications, 1985,pp 83-86. 30. H i l l HF, Mackie AM, Coda BA. Patient-controlled analgesic infusion. Adv Pain Res TIleI' 1 8: 507-523, 1991. 31. Yaksh TL, Rudy TA. Analgesia mediated by a direct spinal action of narcotics. Science 1 92; 1357-1358, 1976. 32. Cousins MJ, Mather LE. Intrathecal and epi dural administration of opioids. Anesthesiology 6 1 : 276-310, 1984. 33. Gambling DR, Yu P, Cole C, McMorland GH, Palmer L. A comparative study of patient controlled epidural analgesia (PCEA) and continuous infusion epidural analgesia (CIEA) during labour. Can J Anaesth 35: 249-254, 1988.