The intrinsic efficacy of opioid analgesics has been suggested to play a role in the development of tolerance to these agents. However, the effect of differences in dosing protocol on tolerance to opioid analgesics of high or low efficacy has not been addressed. Therefore, the effect of opioid intrinsic efficacy on tolerance in mice was determined in protocols of continuous and intermittent administration of equieffective doses of opioid agonists.
Initial antinociceptive median effective doses (ED50s) for five opioid agonists that vary in intrinsic efficacy were estimated in untreated mice. Groups of mice received continuous infusions of morphine, fentanyl, or etorphine for 72 h or 7 days from osmotic minipumps implanted subcutaneously. The infusion doses were calculated as multiples of the initial antinociceptive ED50. An inert placebo was implanted subcutaneously in controls. At the end of treatment, the pumps and placebos were removed, and 4-24 h later, mice were tested in dose-response studies (tail flick) using the same drug that had been chronically administered. In another study using intermittent dosing, mice received subcutaneous injections every 24 h for 3 days of saline or morphine, etorphine, fentanyl, oxycodone, or meperidine, or received subcutaneous injections every 24 h for 7 days of saline or morphine, etorphine, or fentanyl. Daily doses were calculated as multiples of the initial antinociceptive ED50. Twenty-four hours after the last injection, mice were tested in dose-response studies.
High-intrinsic-efficacy compounds (e.g., etorphine and fentanyl) produced less tolerance than a lower-intrinsic-efficacy drug (morphine) in 72-h and 7-day infusion studies. Tolerance for all compounds after intermittent treatment with equieffective doses was similar, and intrinsic efficacy had no effect on the magnitude of tolerance after intermittent dosing.
These results indicate that the intrinsic efficacy of opioid analgesics is inversely related to the degree of tolerance after continuous infusion, but that intrinsic efficacy does not significantly affect tolerance after once-daily intermittent administration of these agents. These findings may be of clinical utility in understanding the development of tolerance to the antinociceptive effects of opioids.
Key words: Analgesia, opioid: continuous infusion; intermittent administration; intrinsic efficacy; tolerance. Analgesics, opioid: etorphine; fentanyl; meperidine; morphine; oxycodone.
PREVIOUS studies have suggested that the intrinsic efficacy of an opioid analgesic can determine, in part, the degree of tolerance to that agent. Specifically, animal studies have demonstrated that the tolerance that develops to equieffective doses of opioid analgesics with high intrinsic efficacy is less than the tolerance that develops to lower-intrinsic-efficacy compounds. [1–4].
Intrinsic efficacy is a property of a particular drug- receptor interaction and is directly related to the number of spare receptors (i.e., receptor reserve), such that the larger the receptor reserve, the greater the intrinsic efficacy.  In cases in which there is a receptor reserve, a criterion response (e.g., maximal response) can be produced with less than full receptor occupancy. The concept of receptor reserve can be illustrated experimentally by alkylating a fraction of receptors and then demonstrating that the dose- response function is simply shifted to the right without any decrease in the maximal response. [6–9].
With regard to opioid tolerance, it has been suggested that equieffective doses of opioid agonists of high or low intrinsic efficacy should produce differential degrees of tolerance because different fractional receptor occupancy is required.  Because it is assumed that tolerance is a consequence of receptor activation, a low-intrinsic- efficacy agonist occupies and produces a “tolerance effect” at more receptors than does a high-efficacy agonist. Therefore, it is predicted that a high-efficacy compound will leave more receptors in the non- tolerant state and produce a smaller degree of tolerance than will an equieffective dose of a low-intrinsic-efficacy agonist. In general, this prediction has been supported by studies that show that high-efficacy opioid agonists (e.g., [D-ala2, N-methyl-phe4, gly-ol5] enkephalin, sufentanil, and fentanyl) produced less tolerance than intermediate- or low-intrinsic-efficacy agonists (e.g., morphine, meperidine, and [D-ala2, D-leu5] enkephalin). [1–4].
That less tolerance may result from equieffective doses of high-intrinsic-efficacy compounds may be an important issue in pain management. However, the majority of studies that have examined this issue in laboratory animals have used continuous administration (i.e., infusion) protocols. [1–4] Because intermittent administration of opioid analgesics is common, it is of interest to determine whether the inverse relation between intrinsic efficacy and tolerance observed in infusion studies holds under noncontinuous administration protocols. Therefore, in the current study we investigated the degree of tolerance after continuous and intermittent administration of equieffective doses of several opioid agonists. In these experiments we show in mice that intrinsic efficacy [6,10–13] interacts with the type of dosing protocol (intermittent vs. continuous) in determining the degree of tolerance to the antinociceptive effects of opioids.
Materials and Methods
Male Swiss Webster mice (22–35 g)(Taconic Farms, Germantown, NY) were used throughout the study. Mice were housed 10 or 11 per cage with free access to food and water and were used only once. All protocols and procedures were approved by the St. John's University Institutional Animal Care and Use Committee.
Initial Estimation of Median Effective Doses
Untreated mice were tested for antinociception (tail flick, see below) in dose-response studies, and the median effective doses (ED sub 50 s) for morphine, etorphine, fentanyl, meperidine, and oxycodone were calculated (Table 1). Four or more different doses of each drug were administered (n = 5–10 mice/dose), and mice were tested for antinociception (see below) 30 min (morphine) or 15 min (all other drugs) after subcutaneous administration. As shown in Figure 1, the dose-response functions obtained in untreated mice for each of the five opioids used in these studies appeared parallel to one another. Probit analysis (see Data Analysis, below) confirmed that there was no significant deviation from parallelism for any dose-response function (P > 0.20). The dosing protocols for tolerance induction were based on these initial ED50s and were designed to deliver equieffective doses of each drug. Specifically, the dosing schedules were defined as multiples of the initial antinociceptive ED50value. This strategy was based on the principle that the ED50value for all drugs is equieffective, by definition, and that therefore multiples of the ED50also are equivalent. For example, 10 times the ED50for morphine was a dose equivalent to 10 times the ED50for etorphine or fentanyl.
Dose-response studies were conducted by means of two procedures: standard and cumulative dosing. In the standard procedure, separate groups of mice (typically 30–40 per group) received subcutaneous injections with three or more different doses of a drug and were tested for antinociception (see below) at the time of peak effect (30 min for morphine and 15 min for all other drugs). Peak effect times were based on time-action profiles determined earlier (data not shown).
In the cumulative dose-response protocol, all mice in a treatment group (typically seven to ten per group) received subcutaneous injections with a starting dose of agonist and were tested for antinociception 30 min (morphine) or 15 min (all other drugs) after administration of opioid agonists. All mice responding to the painful stimulus were given a second dose of the same drug within 15 min of testing and then were retested for antinociception. This cumulative dose-response protocol was continued until all mice failed to respond. The actual doses given for each drug and the strategy for choosing doses in the cumulative dose-response protocol were determined from previous studies. [1,6,14] Data from cumulative dosing are presented such that the percentage of mice that were antinociceptive is plotted against the total (cumulative) dose administered. In most cases, the ED50determined in cumulative dose-response studies was greater than that determined in standard dose-response studies.
Antinociception was determined with a tail-flick assay, as previously described.  A beam of light was focused on the dorsal surface of the tail of the mouse and the apparatus adjusted so that baseline tail flicks occurred within 2–4 s. In dose-response studies, a cutoff tail-flick latency (10 s) was used to avoid tissue damage. Mice that did not flick their tails within 10 s were considered antinociceptive. Testing was conducted without knowledge of the treatment group of each mouse.
Induction of Tolerance
Two dosing strategies were used to induce tolerance: an intermittent protocol and a continuous infusion protocol. In the intermittent dosing protocol, mice received subcutaneous injections once per day for 3 or 7 days with a dose of opioid agonist that was a multiple of the initial ED50(Table 1). In the continuous infusion protocol, mice received subcutaneous infusions from an implanted osmotic minipump for 3 or 7 days with a dose of opioid agonist that was a multiple of the initial ED50. In all experiments, a parallel control group was included as an internal reference for potency changes for the treated group. To minimize the costs associated with the use of the osmotic infusion pumps, an inert placebo pellet was implanted subcutaneously in control mice. Preliminary studies showed that the implantation of placebo pellets produced no effect on morphine's antinociceptive ED50when compared with the ED50determined in mice with a pump infusing saline for 7 days (ED502.54 mg *symbol* kg sup -1 [95% confidence limits 1.78–3.42] and ED502.70 mg *symbol* kg sup -1 [95% confidence limits 1.91–3.63], placebo pellet, saline infusion, respectively).
Intermittent Administration of Opioid Agonists.
Seventy-two-hour Intermittent Administration. Mice (n = 45- 50 per group per experiment) received subcutaneous injections once per day for 3 days of saline, morphine, etorphine, fentanyl, meperidine or oxycodone. The dose of each drug for each injection was based on the initial estimate of the ED50such that [nearly equal] 20 times the ED50(Table 1) was administered on days 1 and 2 and [nearly equal] 40 times the ED50on day 3. The daily doses for the first 2 days and the 3rd day, respectively, were morphine 25.0 and 50.0 mg *symbol* kg sup -1; etorphine 12.0 and 24.0 micro gram *symbol* kg sup - 1; fentanyl 260 and 520 micro gram *symbol* kg sup -1; oxycodone 18.0 and 36.0 mg *symbol* kg sup -1; and meperidine 102.6 and 205.2 mg *symbol* kg1. On day 4 (72 h after the first injection), mice were tested for analgesia in a dose-response study (standard protocol) using the same drug that was chronically administered. To determine the effect of a larger dose of morphine, mice (n = 30 per group) received subcutaneous injections of saline or a morphine dose [nearly equal] 40 times (50 mg *symbol* kg sup -1) the ED50on days 1 and 2 and [nearly equal] 80 times (100 mg *symbol* kg1) the ED50on day 3. Twenty-four hours after the last injection (72 h after the first injection), mice were tested for antinociception.
Seven-day Intermittent Administration.
Mice (n = 7–10 per group per experiment) received subcutaneous injections of saline, morphine (13.7–27.4 mg *symbol* kg sup -1), etorphine (6.2–16.0 micro gram *symbol* kg sup -1), or fentanyl (6.6–660.0 micro gram *symbol* kg sup -1) every 24 h for 7 days. These daily doses are [nearly equal] 5–25 times the initial estimate of the ED sub 50. On day 8 (24 h after the last injection), mice were tested for antinociception in a cumulative dose-response study using the same drug that was injected chronically.
Continuous Infusion of Opioid Agonists. Seventy-two-hour Continuous Infusion.
In mice (n = 7 - 10 per group per experiment) an osmotic minipump (ALZET 2001, Alza, Palo Alto, CA) that delivered pump contents at a rate of 1.0 micro liter *symbol* h sup -1 was implanted subcutaneously. An inert placebo pellet was implanted subcutaneously in control mice. Pumps were filled with morphine (33.33 mg *symbol* kg sup -1 *symbol* day sup -1), etorphine (16 micro gram *symbol* kg sup - 1 *symbol* day sup -1), or fentanyl (347.10 micro gram *symbol* kg sup - 1 *symbol* day sup -1). The infusion doses were equal to the total dose of drug delivered during the 72-h intermittent dosing protocol (see above). Thus, an equivalent dose was administered continuously rather than intermittently. The daily infusion dose represented [nearly equal] 27 times the ED50dose for each drug. Pumps and pellets were left in place for 72 h and then removed, and 4 h later, cumulative dose- response studies were conducted using the same drug that had been infused.
Seven-day Continuous Infusion.
In mice (n = 7–10 per group per experiment) osmotic minipumps (ALZET 2001 or 2002, Alza) delivering contents at a rate of 1.0 micro liter *symbol* h sup -1 or 0.05 micro liter *symbol* h sup -1, respectively, were implanted subcutaneously. An inert placebo pellet was implanted subcutaneously in control mice. Pumps were filled with morphine (13.70–41.10 mg *symbol* kg sup -1 *symbol* day sup -1), etorphine (15.50–124 micro gram *symbol* kg sup -1 *symbol* day sup - 1), or fentanyl (165–1,320 micro gram *symbol* kg sup -1 *symbol* day sup -1), representing a dose range of [nearly equal] 10–200 times the initial ED50s. Pumps and pellets were left in place for 7 days and then removed, and 24 h later, cumulative dose-response studies were conducted using the same drug that had been infused.
Etorphine hydrochloride and inert placebo pellets were obtained from Research Triangle Institute (Research Triangle Park, NC) through the Research Technology Branch of the National Institute on Drug Abuse. Fentanyl citrate and oxycodone hydrochloride were obtained from Sigma Chemical (St. Louis, MO). Morphine sulfate and meperidine hydrochloride were supplied by Penick Corporation (Newark, NJ). All drugs were dissolved in 0.9% sodium chloride and administered subcutaneously. Doses are expressed as the base. Pellets and osmotic minipumps were implanted subcutaneously at the nape of the neck. Pumps and pellets were implanted and removed while mice were lightly anesthetized with halothane/oxygen.
Quantal dose-response data were analyzed by probit analysis  with use of a computer program (BLISS 21, Department of Statistics, University of Edinburgh, Edinburgh, Scotland) that estimates ED50s, 95% confidence limits, and relative potencies and determines whether dose-response functions are parallel. Significant differences between potency estimates and ED50s were determined by probit analysis.
Tolerance after Continuous Infusion
Continuous infusion of morphine, etorphine, or fentanyl for 72 h produced significant tolerance to all three agonists (Figure 2and Table 2). The 72-h morphine infusion generated a 3.3-fold decrease in morphine potency, whereas etorphine and fentanyl infusions produced [nearly equal] 2-fold shifts in potency. The degree of tolerance was significantly greater for morphine than for etorphine or fentanyl.
In the 7-day infusion study, morphine, etorphine, and fentanyl produced significant tolerance after all or most dosing schedules (Figure 3and Table 3). However, doses of morphine much smaller than those of fentanyl or etorphine were required to produce equivalent tolerance. The relation between the multiple of ED50(i.e., chronic dose) and the shift in the ED50(i.e., tolerance) for morphine, fentanyl, and etorphine is presented in Figure 4, in which it can be seen that the curve for morphine is located to the left of the curves for fentanyl and etorphine.
Tolerance after Intermittent Dosing
Intermittent treatment with opioid agonists for 72 h significantly decreased the antinociceptive potency of each of the five opioids (Figure 5and Table 4(A)). (In this 72-h intermittent administration experiment, testing of the mice with the standard dose- response protocol rather than the cumulative protocol accounts for the lower ED50estimates; see Materials and Methods.) The dosing schedule of [nearly equal] 20 times the ED50on days 1 and 2 and [nearly equal] 40 times the ED50on day 3 produced similar tolerance for the five agonists (potency shift range 1.52–1.95). There were no significant differences among these potency shifts. When a larger intermittent dosing schedule for morphine was used (Figure 5, top middle, and Table 4(B)), greater tolerance was observed (3.40- fold). Dosing at higher multiples of the ED50was not attempted for the other drugs because of toxicity. Mortality using the above dosing schedule was 0% for oxycodone, < 1% for both morphine dosing protocols, 11% for meperidine, 6% for etorphine, and 16% for fentanyl.
In the 7-day intermittent administration study (Figure 6and Table 5), equieffective dosing produced approximately similar tolerance for all drugs, suggesting that there was little relation between intrinsic efficacy and the degree of tolerance. For example, 10 times the ED50treatment for morphine and etorphine produced no significant tolerance, but 20 times the ED50dose produced equivalent and significant tolerance. (However, 10 times the ED50treatment for fentanyl resulted in significant tolerance.) Doses of fentanyl and etorphine 25 times the ED50also produced equivalent and significant tolerance. Larger doses of fentanyl and etorphine could not be used for acute daily administration because of the toxicity of larger doses. Specifically, mortality was 0% for all doses of morphine, 20% at 25 times the ED50for etorphine, and 26% for 25 times the ED sub 50 for fentanyl; mortality was 0% for the lower dosing schedules for both fentanyl and etorphine.
The relation between the multiple of ED50and the shift in the ED50for 7-day intermittent dosing is presented in Figure 7. The effect of dose on the degree of tolerance is relatively small compared with that in the 7-day infusion studies (Figure 4). Furthermore, the magnitude of tolerance for all three drugs in the 7- day intermittent dosing protocol was less than that in the infusion studies; however, this discrepancy may have occurred because larger doses could be administered in the infusion studies than could be administered in the intermittent protocols.
The contribution of the intrinsic efficacy of opioid agonists to the development of antinociceptive tolerance in the mouse was examined in the current study in continuous infusion and intermittent dosing protocols. Intrinsic efficacy was inversely related to tolerance after continuous infusion of morphine, etorphine, or fentanyl. These results confirm in mice the findings of previous investigators in rats, in which infusions of high-intrinsic-efficacy opioids (e.g., fentanyl and sufentanil) were associated with less tolerance than were infusions of lower-intrinsic-efficacy opioids (e.g., morphine). [1–4].
In contrast to continuous infusion, intermittent administration of equieffective doses of opioid agonists produced approximately the same degree of tolerance in all of the agents tested. In the 72-h intermittent treatment study, an equieffective dosing schedule was used for five opioids (morphine, fentanyl, oxycodone, meperidine, and etorphine; see Table 4). This dosing protocol resulted in comparable tolerance (1.52–1.95-fold) to all five drugs. Likewise, similar tolerance to morphine, etorphine, and fentanyl was produced by equieffective 7-day intermittent dosing (Table 5). Tolerance was increased in the 72-h intermittent study when the daily dose of morphine was increased, indicating that the magnitude of tolerance was sensitive to dose. (Larger intermittent doses of fentanyl or etorphine could not be evaluated because of the toxicity associated with acute administration of doses in excess of [nearly equal] 25 times the ED50.) It is notable that intermittent administration of morphine in rats is associated with a reduced level of naloxone-precipitated withdrawal compared with that associated with continuous administration of an equivalent amount of drug.  Thus, both tolerance and dependence appear to be related to the degree of intermittency of drug administration.
Intrinsic efficacy is a property of a drug-receptor interaction and is proportional to the number of receptors required to produce a given effect.  Measurement of intrinsic efficacy is a laborious process, and the intrinsic efficacy in vivo of the vast majority of opioid analgesics has not been determined. However, in studies with irreversible micro-receptor antagonists, it has been shown that the intrinsic efficacy of morphine is lower than that of fentanyl. [6,12] Behavioral data from a drug discrimination study suggest that the intrinsic efficacy of meperidine is lower than that of morphine.  Although data on the intrinsic efficacy in vivo of etorphine are not currently available, parallel binding and analgesia studies imply that etorphine has greater intrinsic efficacy than does morphine.  Finally, there is no information currently concerning the intrinsic efficacy of oxycodone. Although the intrinsic efficacies of all opioid analgesics are not known, the finding that all five opioid agonists produced similar tolerance after 72-h intermittent administration suggests that intrinsic efficacy is not an important determinant of tolerance in this dosing protocol. For morphine, etorphine, and fentanyl, which have been shown to differ in intrinsic efficacy, there was a clear difference in the magnitude of tolerance after continuous infusion. Of interest, it has been reported that the degree of analgesic tolerance in rats was similar after acute (8-h) infusions of opioids that vary in intrinsic efficacy (morphine, sufentanil, and alfentanil). [18,19] Thus, the effect of intrinsic efficacy on tolerance after continuous administration appears by 72 h but is not present after an 8- h infusion.
In the 7-day administration studies, the range of dosing schedules for intermittent and continuous administration permitted comparison of the relation between the multiple of ED50(i.e., dose) and the degree of tolerance for continuous and intermittent dosing. As might be predicted, the larger the dose, the greater the degree of tolerance. This relation was most striking for the infusion studies (Figure 4), although there was a weaker relation between dosing and tolerance in the intermittent protocol (Figure 7).
The effect of dosing protocol on the capacity of a drug to produce tolerance can be demonstrated by examining the shift in the ED sub 50 for continuous and intermittent administration. In general, tolerance to morphine (low efficacy) was greater after infusion than after intermittent administration. Specifically (Table 2and Table 4), acute intermittent administration of morphine for 72 h produced a [nearly equal] 2-fold shift in the ED50, whereas infusion of the same dose increased the shift to 3.3-fold. In contrast, the difference between the ED50shifts for intermittent versus continuous administration was less for fentanyl ([nearly equal] 1.7–1.9) and etorphine ([nearly equal] 1.6–2.1). Similarly, (Table 3and Table 5) 7-day morphine infusion of 10 or 20 times the ED50yielded [nearly equal] 2- and 3.4-fold shifts, respectively, whereas intermittent morphine treatment resulted in [nearly equal] 1.4- and 2.4-fold shifts, respectively, in the ED50. In contrast, the magnitude of the ED50shift for fentanyl after intermittent and continuous treatment with 25 times the ED50for 7 days was [nearly equal] 1.9 and 1.6, respectively. Similarly, the magnitude of the ED50shift for etorphine after intermittent and continuous treatment with 25 times the ED50for 7 days was [nearly equal] 1.7 and 1.6, respectively. These results indicate that the degree of tolerance was dependent on both the dosing protocol and the intrinsic efficacy of the drug. In short, the dosing protocol was critical in determining tolerance for the low- efficacy drug.
The compounds used in this study vary significantly in their pharmacokinetic characteristics, and it is possible that kinetic differences may have affected the results, especially after intermittent administration because the duration of exposure of receptors to each drug would differ. For example, etorphine and fentanyl have been shown to have much shorter half-lives than morphine. [10,20,21] In general, however, tolerance was equivalent for all agonists after intermittent dosing. Although it is possible that pharmacokinetic differences among the compounds may affect the degree of tolerance with some dosing protocols, the intermittent protocol used in the current study did not reveal a relation between kinetics and tolerance. In infusion studies, steady-state plasma concentrations would be reached faster with fentanyl and etorphine than with morphine, suggesting that more tolerance might be induced for fentanyl and etorphine. In fact, just the opposite was observed in the infusion studies: tolerance to fentanyl and etorphine was less than that to morphine. These results suggest that kinetic differences among the compounds are not a significant variable in determining the degree of tolerance. In infusion studies the washout of fentanyl and etorphine would be more rapid than that of morphine. This difference may have contributed to the reduced tolerance seen for etorphine and fentanyl, because we allowed 4–24 h between infusion termination and analgesic testing. However, other investigators have shown that intrinsic efficacy affects the degree of tolerance after infusions even when there is no interval between dosing termination and testing.  Thus, our studies extend previous results on the role of intrinsic efficacy in tolerance in infusion studies.
Overall, the current findings indicate that the effects of intermittent administration are different from those of continuous infusion. The mechanism whereby all agonists tested produced roughly equivalent tolerance after intermittent administration is not readily apparent but may be related to phasic versus continuous stimulation of receptors. Perhaps relatively brief elicitation of an equivalent effect by several agonists initiates comparable tolerance mediated by common intracellular substrates (e.g., cyclic adenosine monophosphate, ion flux). Receptor-based contributions (e.g., decoupling) to tolerance after intermittent administration may be minimal because of the alternating periods of receptor occupancy. In contrast, continuous administration may induce changes close to the receptor site (e.g., decoupling) due to uninterrupted receptor occupancy, as well as at other intracellular sites. Whatever the mechanism, infusions of the high- intrinsic-efficacy agonists etorphine and fentanyl produced less tolerance, whereas an equieffective infusion of morphine produced greater tolerance. These findings clearly support the role of intrinsic efficacy in tolerance during continuous administration.
The potential clinical importance of these results is that analgesics of high intrinsic efficacy may produce less tolerance than low-efficacy analgesics when administered as infusions. Therefore, it is possible that there is a clinical advantage to using opioid analgesics of high intrinsic efficacy for continuous administration. However, our results suggest that there may be little benefit in the use of intermittent high-efficacy agonists to reduce tolerance. Furthermore, the current results may be relevant to observations by some investigators that clinical tolerance is a relatively rare phenomenon.  Some clinicians have suggested that the need for increased opioid analgesics may be precipitated more by a change in the underlying pain state (i.e., disease progression) than by tolerance. [23–25] Perhaps the modest incidence or magnitude of clinical tolerance is related to the phasic plasma profiles that accompany intermittent oral and acute parenteral administration. Thus, clinical tolerance may be minimized by the phasic nature of intermittent dosing. In support of this suggestion are clinical case examples of stable intermittent opioid (morphine) use for the treatment of pain, followed by increasing opioid use with the initiation of continuous infusions.  It is worth noting that intermittent spinal administration of morphine for cancer pain has been reported to be associated with more tolerance than spinal infusions.  However, in that report, it is not clear whether total daily dose was equivalent for intermittent and infusion protocols, thus making comparison more difficult.
In summary, the current study has shown that intrinsic efficacy, dose, and dosing protocol interact in determining the degree of tolerance to opioids. Intrinsic efficacy appears to influence tolerance more significantly after continuous administration than after intermittent administration. In general, intermittent administration of equieffective doses of opioid agonists resulted in equivalent levels of tolerance. These findings may be important in identifying the appropriate opioid analgesic for use in infusion and intermittent treatment protocols. Currently, however, the clinical applicability of the these findings remains to be determined empirically.
The authors thank Penick Corporation, for supplying morphine and meperidine, and the National Institute on Drug Abuse, for supplying placebo pellets and etorphine. They also thank K. W. Chan, S. Shah, T. Davis, and G. Munirathinam, for their assistance. Dr. M. T. Turnock's contributions also are appreciated.