Intrathecal Morphine Infusion Research Articles

Long-term intrathecal infusion of morphine in the home care of patients with advanced cancer.

Fear of infections and other complications has made many clinicians avoid intrathecal application of morphine in chronic cancer pain. However, recent comparative studies show that, in long-term treatment, intrathecal morphine administration may give a more satisfactory pain relief with lower doses of morphine and fewer side-effects than epidural administration. In Montpellier Cancer Institute, first cancer pain patients received long-term intrathecal morphine as early as in 1979, and since then more than 400 patients have been treated. In 1991-1994, 50 patients having refractory cancer pain were treated with a continuous intrathecal infusion of morphine using an external pump with patient-controlled boluses. In this retrospective study, the outcome of these 5602 days of morphine therapy will be analysed. The treatment consisted of a lateral puncture technique, strictly aseptic conditions during catheter insertion and changes of pump reservoirs, and effective prevention of side-effects. The average duration of intrathecal infusion was 142 (7-584) days. The mean starting dose, 2.5 (0.4-8.3) mg/day, increased to a mean final dose of 9.2 (1-94) mg/day, the average dose being 5.4 (1-23) mg/day. During the treatment period, no clinically detectable infections and no respiratory depression occurred. Leakage of cerebrospinal fluid followed by post-spinal headache occurred in only 6 patients who received a temporary external catheter: the lateral lumbar puncture technique seemed to protect from this complication in long-term treatment. The patients stayed at home, coming to agreed control visits only at 4-6 week intervals, using a telephone-telefax service for emergencies. Long-term intrathecal morphine infusion seems to provide satisfactory analgesia, few side-effects and a high degree of patient autonomy.

Treatment of Chronic Unstable Angina Pectoris: Use of a Totally Implantable Programmable Device for Continuous Intrathecal Infusion of Opiates: Case Reportxs

We report the case of a 70-year-old man with a 17-year history of angina pectoris, who had previously suffered two documented myocardial infarctions and undergone multiple diagnostic cardiac catheterizations, two coronary artery bypass operations, and several percutaneous transluminal coronary angioplasty procedures. The patient had experienced unstable angina for the past 3 years refractory to maximal medical therapy and was unsuitable for further attempts at revascularization. After a successful trial of epidural infusion of morphine, a totally implantable programmable continuous-infusion device with an intrathecal catheter was implanted in the patient on August 18, 1993, resulting in maintained pain resolution. His gardening, carpentry, and other activities of daily living were limited only by shortness of breath. Six months later, the pump treatment did not mask the development of a myocardial infarction. To the best of our knowledge, this is the first report of the use of continuous intrathecal infusion of morphine or the use of a totally implantable programmable infusion device for angina pectoris. We propose that in carefully selected patients with chronic unstable angina, continuous intrathecal infusion of morphine may relieve effort-induced pain without resulting in myocardial infarction.

Stability and compatibility of baclofen and morphine admixtures for use in an implantable infusion pump

The simultaneous intrathecal infusion of baclofen and morphine may be of significant benefit in the treatment of both severe pain and spasticity. The stability and physical compatibility of baclofen and morphine admixtures, at a range of concentrations relevant to their use for intrathecal administration, have been examined. The studies reported demonstrate that baclofen and morphine in the admixtures examined were stable for at least 30 days when stored at 37°C. In addition, it was shown that admixtures can be introduced into an Infusaid ® implantable infusion pump, used clinically for the intrathecal delivery of drugs, and appropriate concentrations of both baclofen and morphine maintained for a duration of up to 30 days. The data presented indicate that admixtures of baclofen and morphine can be successfully prepared and delivered using an Infusaid ® pump for periods consistent with proposed clinical practice.

Difficult management of pain following sacrococcygeal chordoma: 13 months of subarachnoid infusion

We report on a patient suffering severe pain following a long-standing sacral chordoma in whom management of therapy and pain was extremely difficult. Because orally administered morphine was observed to be ineffective in the early stages of treatment, we tried to achieve pain relief by using epidural morphine. This was also unsatisfactory. Intrathecal infusion of morphine and bupivacaine through a catheter inserted at the L2-L3 level was also found to be ineffective; only a segment block was observed. A structural anomaly of the spine was suspected and confirmed by myelography, showing metastasis at L3. Pain relief improved when an infusion of morphine + bupivacaine was employed through a catheter placed at the L4-L5 level below the blockage. A major problem which continued throughout the course of the disease was the daily occurrence of episodes of unbearable sharp pain that required addition of midazolam to the local anesthetic/opioid subarachnoid infusion. The patient received this mixture through an intrathecal port during the last 13 months of life, a gradually increasing dose being necessary. Periods of analgesia were followed by occasional crises of intense sharp pain suggesting incomplete relief. No serious complications or meningitis occurred. This case emphasizes the difficulty in managing pain in this type of cancer.

Intrathecal morphine in the treatment of chronic intractable pain.

Fifteen patients with intractable pain received intrathecal morphine delivered via a programmable (Medtronic) device. In twelve patients the pain was due to cancer and three patients had pain of non malignant origin. All of the patients reported excellent or good relief. A total of 14 complications were reported in 7 patients. Most of these were minor and related to surgical or mechanical problems. One patient with pain of non malignant origin developed serious complications which required the removal of the infusion device. The results of this study show that chronic intrathecal infusion of morphine is superior to conventional forms of analgesia in patients with intractable pain of malignant origin. We would advise that it should remain a therapy of last resort in patients with intractable non malignant pain as the long term side effects are still unknown and the potential for serious side effects still exists.

Long-term intrathecal infusion of morphine and morphine/bupivacaine mixtures in the treatment of cancer pain: A retrospective analysis of 51 cases

A retrospective analysis of 51 patients with cancer pain treated with a continuous i.t. morphine infusion through a tunnelled percutaneous catheter was undertaken. Because of insufficient pain relief with morphine only, 17 of these patients received a morphine/bupivacaine mixture. Pain relief subsequently improved significantly in 10 patients and a moderate improvement was present in 4 patients. An additional analgesic effect of bupivacaine was not shown in 3 patients with clinical signs of severe mental depression. Bupivacaine-induced side effects were absent below a daily dosage of 30 mg by continuous infusion. In all patients a gradual dose increment was observed. No serious complications, neurologic sequelae or meningitis occurred. It is concluded that long-term i.t. infusion of morphine through a tunnelled catheter can provide adequate pain relief in cancer patients with an acceptable risk-benefit ratio. The effects of long-term intrathecal co-administration of local anesthetics, especially bupivacaine, await further prospective evaluation.

Response of intractable pain to continuous intrathecal morphine: a retrospective study

We have treated 37 patients with intractable pain (35 with cancer-related pain) by continuous intrathecal morphine infusion via implanted pump. These patients were carefully selected according to specific criteria, and each demonstrated a significant reduction in pain following a test dose of intrathecal morphine. All patients had good pain relief from intrathecal morphine infusion, even with pain located in cervical dermatomes. Systemic narcotics could be withdrawn from most patients. Significant side effects were rare and typically self-limited. Many patients required gradually increasing doses, seemingly related to disease progression. Two patients with non-malignant pain have had variable dose requirements over 28 and 44 months without clear tolerance. In these patients we observed a reduction in side effects associated with systemic opioids when continuous intrathecal opioid infusion was instituted. Intrathecal opioid administration may have fewer complications than ablative pain relief procedures. In properly selected patients, this method offers an effective alternative for pain relief.

Sufentanil Citrate and Morphine/ Bupivacaine as Alternative Agents in Chronic Epidural Infusions for Intractable Non-Cancer Pain

Intraspinal narcotic (usually intrathecal morphine) infusions with implanted pumps are increasingly used in patients with intractable chronic pain not caused by cancer. In some patients, pain control is difficult with infusions of morphine. Seven patients with diagnoses of arachnoiditis, epidural scarring, and/or vertebral body compression fracture were treated with alternative solutions in an epidural route. For maximal flexibility, Medtronic implanted programmable infusion pumps with catheters to T6-T10 were used, and pain was monitored by verbal pain scales. In three patients, epidural infusions of morphine in 0.5% bupivacaine (MS-MARC) resulted in little or no pain relief without significant side effects (e.g., headache, nausea, or vomiting). In these same patients, epidural infusions of sufentanil citrate resulted in pain scale reductions of 92%, 82%, and 40%, respectively, with no side effects. Four other patients found more effective pain relief when switched from initial sufentanil citrate infusions to MS-MARC. Pain scale reductions (with no side effects) were 92%, 76%, 59%, and 47% in these patients. Pain relief and minimal side effects with sufentanil citrate is theorized to result from its higher lipophilicity promoting local transdural diffusion to spinal cord and limiting upward diffusion to the brain stem. Sufentanil citrate is also advantageous for programmable pumps because it is 100 times more potent than morphine and therefore allows longer pump refill times and higher infusion doses. Although this study was done on a limited number of patients, sufentanil citrate and MS-MARC in epidural infusions using programmable infusion pumps for non-cancer patients provide significant alternative drug combinations and routes.

Neuropathologic Findings after Long-term Intrathecal Infusion of Morphine and Bupivacaine for Pain Treatment in Cancer Patients

Epidural or intrathecal infusions of morphine and bupivacaine mixtures are presently used for the treatment of "refractory" cancer pain even though the neurotoxic potential of such mixtures is unknown. The pathologic findings of the spinal column, the meninges, the nerve roots, and the spinal cord, and the clinical neurologic deficits were recorded in 15 patients (5 men and 10 women), aged 26-83 (median 68) yr, treated for 4-274 (median 81) days with intrathecal infusions of morphine (with preservatives [sodium metabisulfite and sodium edetate]) and bupivacaine mixtures, given through open, subcutaneously tunneled nylon catheters. Six patients had been subjected to radiation therapy (20-96 Gy), applied over the spinal column, and four had been treated with antineoplastics believed to be neurotoxic. Ten patients had various neurologic deficits before the intrathecal treatment. The cumulative doses (ranges) given intrathecally were: morphine 33-11,900 mg, sodium metabisulfite 3.3-1,050 mg, sodium edetate 0.33-105 mg, and bupivacaine 10-41,400 mg; cumulative volumes were 16-9,400 ml. The concentrations of the drugs in the mixtures were: morphine 0.25-4.0 mg/ml, sodium metabisulfite 0.025-0.40 mg/ml, sodium edetate 0.0025-0.04 mg/ml, and bupivacaine 3.0-4.75 mg/ml. The osmolality of the mixtures in vitro ranged from 282 to 286 mOsm/kg and the pH from 4.1 to 4.6. The pathologic findings consisted of vertebral metastases (n = 6), epidural and/or intrathecal tumor masses (n = 8), focal subdural fibrosis (n = 6), infiltration of mononuclear cells in the subarachnoid space (n = 10), and discrete injuries (nerve fiber degeneration or fibrosis) to the anterior (five patients) and posterior (seven) nerve roots, and spinal cord (tumor compression [one], slight thickening of the leptomeninges [one], and thrombosis of a spinal artery and medullary infarction [one]). In none of the cases was any reaction against the nylon catheter within its subarachnoid course recorded. The neuropathologic findings were not related to the duration or cumulative doses of the intrathecal treatment. No new neurologic deficits that could be attributed to the intrathecal administration of the opiate-bupivacaine mixtures were recorded. The neuropathologic and clinical neurologic findings in cancer patients treated with intrathecal morphine-bupivacaine mixtures appeared similar to those in animals and humans reported with either intrathecal morphine or bupivacaine alone.

Hyperalgesia and myoclonus with intrathecal infusion of high-dose morphine

We report the case of a patient who developed myoclonus and hyperalgesia following administration of high-dose subarachnoid morphine. This complication occurred with 40–80 mg/day continuous infusion. The pathophysiology of these side effects is discussed.

Sufentanil Citrate and Morphine/Bupivacaine as Alternative Agents in Chronic Epidural Infusions for Intractable Non-Cancer Pain

Abstract Intraspinal narcotic (usually intrathecal morphine) infusions with implanted pumps are increasingly used in patients with intractable chronic pain not caused by cancer. In some patients, pain control is difficult with infusions of morphine. Seven patients with diagnoses of arachnoiditis, epidural scarring, and/or vertebral body compression fracture were treated with alternative solutions in an epidural route. For maximal flexibility, Medtronic implanted programmable infusion pumps with catheters to T6-T10 were used, and pain was monitored by verbal pain scales. In three patients, epidural infusions of morphine in 0.5% bupivacaine (MS-MARC) resulted in little or no pain relief without significant side effects (e.g., headache, nausea, or vomiting). In these same patients, epidural infusions of sufentanil citrate resulted in pain scale reductions of 92%, 82%, and 40%, respectively, with no side effects. Four other patients found more effective pain relief when switched from initial sufentanil citrate infusions to MS-MARC. Pain scale reductions (with no side effects) were 92%, 76%, 59%, and 47% in these patients. Pain relief and minimal side effects with sufentanil citrate is theorized to result from its higher lipophilicity promoting local transdural diffusion to spinal cord and limiting upward diffusion to the brain stem. Sufentanil citrate is also advantageous for programmable pumps because it is 100 times more potent than morphine and therefore allows longer pump refill times and higher infusion doses. Although this study was done on a limited number of patients, sufentanil citrate and MS-MARC in epidural infusions using programmable infusion pumps for non-cancer patients provide significant alternative drug combinations and routes. (Neurosurgery 29:76-82, 1991)

Sufentanil citrate and morphine/bupivacaine as alternative agents in chronic epidural infusions for intractable non-cancer pain

Intraspinal narcotic (usually intrathecal morphine) infusions with implanted pumps are increasingly used in patients with intractable chronic pain not caused by cancer. In some patients, pain control is difficult with infusions of morphine. Seven patients with diagnoses of arachnoiditis, epidural scarring, and/or vertebral body compression fracture were treated with alternative solutions in an epidural route. For maximal flexibility, Medtronic implanted programmable infusion pumps with catheters to T6-T10 were used, and pain was monitored by verbal pain scales. In three patients, epidural infusions of morphine in 0.5% bupivacaine (MS-MARC) resulted in little or no pain relief without significant side effects (e.g., headache, nausea, or vomiting). In these same patients, epidural infusions of sufentanil citrate resulted in pain scale reductions of 92%, 82%, and 40%, respectively, with no side effects. Four other patients found more effective pain relief when switched from initial sufentanil citrate infusions to MS-MARC. Pain scale reductions (with no side effects) were 92%, 76%, 59%, and 47% in these patients. Pain relief and minimal side effects with sufentanil citrate is theorized to result from its higher lipophilicity promoting local transdural diffusion to spinal cord and limiting upward diffusion to the brain stem. Sufentanil citrate is also advantageous for programmable pumps because it is 100 times more potent than morphine and therefore allows longer pump refill times and higher infusion doses. Although this study was done on a limited number of patients, sufentanil citrate and MS-MARC in epidural infusions using programmable infusion pumps for non-cancer patients provide significant alternative drug combinations and routes.

Long-term pain relief produced by intrathecal morphine infusion in 53 patients

The present report details the characteristics of the analgesic effects of morphine administered chronically by infusion pumps implanted in 53 patients suffering from terminal metastatic disease. The median postimplant survival time in these patients was 4 months. Patients (mean age 58 years) were characterized according to the duration of pain before pump implantation (mean 16 months), prior consumption of systemic opioids (mean one to six daily analgesic equivalents of morphine), and their response to a trial intrathecal dose of morphine (1 to 2 mg). The median infusion dose at 2 weeks was 3.8 mg/day. The analgesic index, calculated as (quality of pain relief x duration of pain relief in hours)/morphine dose in mg, that was observed after the trial dose of morphine was determined for each patient. A close correlation was observed between the acute (2-week) infusion dose necessary to produce pain relief and the analgesic index such that the infusion dose = -8.0 x log (analgesic index) + 17.1. By 16 weeks, the mean spinal morphine dose for the group had increased by a factor of about 2.5; however, significant variation in the dose incrementation was documented. The maximum increase was observed in patients with a low analgesic index, and this rapid incrementation was usually correlated with an unsatisfactory overall outcome. Evidence that long-term infusion continues to yield analgesia was evidenced in six cases where there was an unanticipated loss of drug infusion and a corresponding increase in parenteral narcotic consumption. These data indicate the long-term efficacy and safety of spinal opioid infusion in patients with terminal cancer, and emphasize the advantage of assessing the sensitivity of the patient to spinal opioids by a standardized trial injection prior to pump placement as a prognostic indication of outcome.

Comparison of subjective and objective analgesic effects of intravenous and intrathecal morphine in chronic pain patients by heat beam dolorimetry

The pain tolerance latencies of 10 chronic pain patients were evaluated by heat beam dolorimetry (stimulus intensity 15.33 mW · cm −2 · sec −1) prior to and following administration of morphine by intrathecal (n = 5) or intravenou Patients not undergoing opiate withdrawal evinced increased baseline pain tolerance latencies prior to drug administration compared with normal volunteers. Two patients undergoing the opiate withdrawal syndrome at the time of test experienced reduced pain tolerance latencies compared with normal volunteers, most probably corresponding to the hyperesthesia symptom of the syndrome. Intravenous morphine infusion (30 mg) induced a time-dependent increase in cutaneous pain tolerance with peak effect occurring 1–2 h after administration. This persisted for up to 4 h and thereafter declined. The time course of subjective pain self-report by visual pain analog scale (VPAS) measurements corresponded to the time course of increasing cutaneous pain tolerance latency assessed by dolorimetry. Pain self-reports following intrathecal morphine infusion (2.25 or 1 mg) followed a similar though slower onset to that reported by patients receiving intravenous morphine and was of lesser degree. In contrast, heat beam dolorimetric evidence of increased cutaneous pain tolerance (which was of lesser degree than following i.v. morphine) did not reach its maximum during the 4 h measuring period. A dissociation was noted therefore between the self-reported relief of endogenous pain and dolorimetrically measured cutaneous analgesia following intrathecal morphine administration. Linear regression correlation analysis characterized this phenomenon as a positive correlation between cutaneous pain tolerance and pain relief self-report following intravenous morphine infusion and a negative correlation following intrathecal administration. We propose that the phenomenon may be due to intrathecal morphine acting via two separate compartments: one spinal and one supraspinal. We further propose that the prolonged segmental action of intrathecal morphine is continued through supraspinal processes, which induce dolorimetrically measurable elevation of pain tolerance level.

Magnitude of opioid dependence after continuous intrathecal infusion of μ- and δ-selective opioids in the rat

The continuous intrathecal infusion of morphine (2, 6, 20 nmol/h), sufentanil (0.06, 0.2, 0.6 nmol/h), [D- Ala 2,MePhe 4, Glu-ol 5]enkephalin (DAMGO) (0.1, 0.3, 1.0 nmol/h) or [D-Ala 2,D-Leu 5]enkephalin (DADLE) (2, 6, 20 nmol/h) in unanesthetized rats produces a dose-dependent increase in hot plate latency 1 day after pump implant followed by a gradual return to baseline values by days 3–4, i.e. tolerance. Rats assessed for opioid dependence after 7 days of intrathecal (i.t.) infusion of opioids show a withdrawal syndrome most readily noted by withdrawal body shakes (WBS) after injection of the opioid antagonist, naloxone (1 mg/kg i.p.). The number of WBS was proportional to the infusion dose of opioid agonist. Although each tolerance-producing agent was infused in one of three log-spaced (low, medium, high) doses, selected to have approximately equal antinociceptive activity across agents, the agents varied in the apparent degree of dependence. Thus, at the highest infusion dose, the average number of WBS observed was greatest for DADLE (32.8), morphine (30.2) and sufentanil (25.0) while animals treated with DAMGO displayed a significantly less degree of opioid dependence (8.7).

A study of the interaction between clonidine and morphine on analgesia and blood pressure during continuous intrathecal infusion in the rat

In the rat, the continuous intrathecal (i.t.) infusion of clonidine (0.4 μg/hr) significantly increased the tail-flick latency (TF) and the threshold for paw pressure (PP) withdrawal for 5 days and decreased the systolic blood pressure (up to 24 mm Hg) for 7 days. The antinociceptive effect of continuous intrathecal infusion of clonidine (0.4 μg/hr) in the tail flick and paw pressure tests was not attenuated in rats that were tolerant to morphine. The acute intrathecal administration of clonidine (2.7 μg) and morphine (1.0 μg) resulted in a synergistic interaction in the tail-flick and paw pressure tests. A synergistic interaction was also observed during the continuous intrathecal infusion of morphine (1.25 μg/hr) and clonidine (0.2 μg/hr) in the tail-flick and paw pressure tests. Individually, these doses of morphine and clonidine had no antinociceptive effect. However, intrathecal infusion together yielded peak tail-flick and paw pressure responses comparable to that of 0.4 μg/hr clonidine alone, without affecting systolic blood pressure. No delay in the onset of tolerance to the analgesic effect was observed with the combination as compared with clonidine (0.4 μg/hr) alone. The data indicate that clonidine-induced spinal analgesia is independent of endogenous opioid systems linked to μ-receptors in the spinal cord, and that optimization of spinal analgesia (e.g. synergism) can be achieved during continuous intrathecal infusion without affecting cardiovascular activity.

Investigation of tolerance to chronic intrathecal morphine infusion in the rat

Rats received chronic subcutaneous or intrathecal infusions of either saline or 25 μg/μl/hr or 50 μg/μl/hr of morphine sulfate. During five days of infusion individual groups of rats were assessed on either the nociceptive tail flick or hot plate test. After the infusions, the analgesic effects of either subcutaneous or intrathecal morphine test doses were evaluated. Tolerance developed to the analgesic effect of both subcutaneous and intrathecal morphine infusions on the tail flick test. Subcutaneously infused rats were also tolerant to a subcutaneous morphine challenge on this test. However, intrathecally infused rats were not tolerant to either the subcutaneous or intrathecal challenge. In contrast to these results, rats tested on the hot plate were not analgesic in response to either subcutaneous or intrathecal morphine infusions. However, these rats were tolerant when challenged with either subcutaneous or intrathecal morphine. The results are discussed in terms of the relative contribution of spinal and supraspinal sites to opiate tolerance, and the possibility that tolerance does not develop to the antinociceptive effect of spinal morphine on spinally mediated reflexes.

Analgesia and tolerance to intrathecal morphine and norepinephrine infusion via implanted mini-osmotic pumps in the rat

The objectives of this study were to investigate the duration of analgesia and the development of tolerance following continuous intrathecal administration of morphine and norepinephrine alone, and morphine followed by norepinephrine via mini-osmotic pumps in the rat. Analgesia was assessed by the tail-flick test. In single pump experiments morphine 1 μl (10 μg)/h (7 days) and 0.5 μl (10 μg)/h (14 days) produced analgesia with tolerance by days 5–7. Norepinephrine 1 μl (15 μg)/h (7 days) produced analgesia equivalent to that of morphine with tolerance developing by day 3. Following continuous intrathecal morphine 1 μl (10 μg)/h for 5 days, norepinephrine 1 μl (15 μg)/h for 7 days failed to produce a significant increase in analgesia. This was in contrast to the increase in analgesia seen when the norepinephrine infusion followed a saline infusion. Determination of the norepinephrine concentration in the solution from the osmotic pumps verified that the norepinephrine is stable for the treatment period.

Outcomes and complications of continuous intraspinal narcotic analgesia for cancer pain control.

Preliminary reports of continuous intraspinal morphine analgesia have been enthusiastic regarding the resultant cancer pain control. Reports of continuous intraspinal infusion have not documented the duration of useful analgesia, need for concomitant analgesic therapies, or complication rates. Thus, the overall outcomes and complications of six chronic intrathecal and eight epidural morphine infusions were analyzed in the first 14 cancer pain patients implanted with continuous intraspinal morphine infusion reservoirs at this clinic. A five-point scale was used to assess the analgesic therapy required to maintain pain control during three consecutive intervals of intraspinal morphine infusion (zero to two months, two to six months, after six months). Comparison with pre-implant narcotic requirements revealed equal or reduced narcotic use for up to six months of therapy, with a definite trend toward escalation of intraspinal narcotics, systemic analgesia, and adjunctive procedures after two months. This occurred most likely due to narcotic tolerance and disease progression. Failure of pain control was the rule with continuous intraspinal morphine after six months. Three patients ultimately required neurolytic blocks. No clear difference was found in pain control requirements between epidural and intrathecal morphine infusion. No infection or respiratory depression occurred as a direct result of the intraspinal morphine implanted system.

Partial cross tolerance to D-Ala 2-D-Leu 5-enkephalin after chronic spinal morphine infusion

The development of tolerance to morphine and cross tolerance to D-Ala 2-D-Leu 5-enkephalin (DADL) at spinal cord level to the inhibition of tail flick response was studied in rats tolerant to morphine. The long term intrathecal infusion of morphine sulfate was accomplished by means of an osmotic minipump. Intrathecal infusion of morphine sulfate (2 μg/hr) markedly elevated the tail flick latency measured 24 hr after the start of infusion. The increased tail flick latencies gradually decreased during 6 days of intrathecal infusion of morphine sulfate. Tolerance to morphine and DADL was determined by inhibition to the tail flick response after intrathecal administration of cumulative doses of morphine sulfate and DADL. Chronic intrathecal infusion of morphine induced a marked tolerance to morphine but developed only a slight cross tolerance to DADL. The results indicate that there exists two separate types of opioid receptor, μ- and δ-opioid receptor in the spinal cord of rats.