Does intrathecal morphine in the treatment of cancer pain induce the development of tolerance?

OBJECTIVE: This retrospective study was designed to investigate whether chronic lumbar intrathecal administration of morphine leads to the development of opioid tolerance in patients suffering from intractable cancer pain. METHODS: Between 1978 and 1995, 159 patients with refractory cancer pain were treated with intrathecal morphine in our Multidisciplinary Pain Center. The treatment consisted of preservative-free morphine administered through an access port as a single bolus. In this series of patients (n = 159), the daily doses of intrathecal morphine were determined as a function of duration of follow-up. RESULTS: The mean follow-up period was 95 days (range, 5-909 d), the mean starting daily dose of intrathecal morphine was 2.69 mg (range, 1-7.5 mg), and the mean terminal dose was 7.82 mg (range, 1-80 mg). The results demonstrated that only a moderate increase in daily dose of intrathecal morphine was required during the course of treatment (a two- to threefold increase for a 3-mo period). Furthermore, the dose increment was similar for patients followed up for more or less than 60 days. This increase did not result in any central opioid-related side effects, and the pain was managed satisfactorily. CONCLUSION: The requirement for a moderate increase in intrathecal opioid doses reflects the development of tolerance but did not limit the patients' ability to obtain adequate analgesia during the course of their painful disease.     

Spinal cord compression by catheter granulomas in high-dose intrathecal morphine therapy: case report

OBJECTIVE AND IMPORTANCE: The use of chronic intrathecal morphine for the treatment of intractable, nonmalignant pain is becoming more prevalent. A rare but devastating complication of this therapy is the development of spinal cord compression secondary to the formation of intrathecal granulomas. CLINICAL PRESENTATION: We report three cases of intrathecal granuloma formation in the thoracic subarachnoid space, associated with intrathecal morphine pumps. These three patients were receiving high doses of morphine to control their pain (25 mg/d, 28 mg/d, and 45 mg/d, respectively) when they presented with signs and symptoms of thoracic spinal cord compression. Myelography and postmyelographic computed tomography of the spine revealed masses causing spinal cord compression. INTERVENTION: Two patients underwent thoracic laminectomies for resection of these masses, and the other patient had the intrathecal catheter removed. A pathological examination revealed sterile granulomas in the resected masses. CONCLUSION: Intrathecal granulomas are likely to occur with increasing frequency as the use of chronic intrathecal morphine delivery increases in patients with nonmalignant pain. The cause of intrathecal granulomas is unknown, although it is likely that morphine plays a major role in their formation. We think that those patients receiving high doses of morphine are at greater risk for developing this complication.     

Evaluation of the safety and efficacy of ketorolac versus morphine by patient-controlled analgesia for postoperative pain

STUDY OBJECTIVE: To compare ketorolac tromethamine with morphine for pain management after major abdominal surgery. DESIGN: Double-blind, randomized study. SETTING: Hospital recovery room and postoperative surgical unit. PATIENTS: One hundred ninety-one patients with at least moderate pain after major abdominal surgery. INTERVENTIONS: Patients received ketorolac by patient-controlled analgesia (PCA) bolus alone (Ket B), ketorolac by bolus plus infusion (Ket I), or morphine by PCA bolus (morphine), with injectable morphine available for supplementation. MEASUREMENTS AND MAIN RESULTS: Levels of sedation, pain intensity, pain relief, and adverse events were recorded at baseline, at 2, 4, and 6 hours, and at termination. Supplemental morphine was required by 71% of Ket B patients, 67% of Ket I patients, and 38% of morphine patients (p < or = 0.001 for Ket B vs morphine). Although patients receiving ketorolac required more supplemental morphine than the morphine group (6.0 mg Ket I, 6.2 mg Ket B, 4.0 mg morphine), there was a large morphine-sparing effect in both ketorolac groups (total morphine 6.0 mg Ket I, 6.2 mg Ket B, 33.3 mg morphine). Overall pain relief scores were similar for morphine and Ket I groups, and were lower for Ket B than for morphine (p = 0.002). There were no differences among groups in numbers of patients with adverse events. CONCLUSION: Ketorolac may be effective when administered by PCA device, and has a clear morphine-sparing effect.     

Restricted expression of Fc gammaRIII (CD16) in synovium and dermis: implications for tissue targeting in rheumatoid arthritis (RA)

The authors conducted a prospective randomised double-blind comparison of patient-controlled analgesia (PCA), with a combination of morphine and ketorolac versus morphine alone and ketorolac alone in the management of postoperative pain after orthopaedic surgery. Forty-two patients were randomly assigned to three groups. Group 1 was given 1 mg/ml morphine, group 2 was given 3 mg/ml ketorolac and group 3 half-doses of each. After a loading dose of 0.07 ml/kg, PCA was started at an initial setting of 1 ml per demand, with a 10-min lock-out interval and no background infusion. Pain was measured at rest and during movements for 48 h. The combination of morphine and ketorolac was more effective than morphine or ketorolac alone in relieving rest pain throughout the study. The combination was also more effective during movement than either drug alone, but only for the first 24 h. The consumption of morphine and ketorolac was significantly lower when the two drugs were administered together. The incidence of urinary retention was highest in the group given morphine alone. The combination of half-doses of morphine and ketorolac is more effective in controlling postoperative pain than either drug alone. This combination also reduces analgesic consumption and morphine-related adverse events.     

Respiratory depression following administration of intrathecal bupivacaine to an opioid-dependent patient

OBJECTIVE: To document two cases of respiratory depression in patients receiving morphine once the stimulating effect of pain on respiration was removed by bupivacaine. CASE SUMMARIES: Case 1: A 72-year-old 84-kg white man with cancer of the bladder and bone metastases had intense back and leg pain that was treated with intrathecal morphine for 6 months at an increasing dosage up to 10 mg twice daily. The intrathecal route was avoided for 4 days because of a suspected local infection at the site of the intrathecal catheter. During this 4-day period the patient received extended-release morphine and subcutaneous morphine daily. When the intrathecal route was used again, he received an identical dose of morphine plus bupivacaine and epinephrine. Ten minutes after the injection, fatal respiratory distress occurred. Case 2: A 92-year-old white woman was admitted for revascularization of arteritis on her left leg. To treat a painful sacrum and heel bedsores, she received extended-release oral morphine for 8 days. Induction of the intrathecal anesthesia was performed with bupivacaine. After 10 minutes, the patient became subcomatose, with miosis and apnea. Intravenous naloxone restored spontaneous respiration and normal consciousness. CONCLUSIONS: Pain is a physiologic antagonist of the respiratory depressant effects of opioid analgesics. By reducing pain stimulation, bupivacaine may make patients more susceptible to opioid respiratory depression. Such situations require titration of bupivacaine and other analgesics as well as increased monitoring of the patient.     

First record of trypanosomes in Tasmanian bandicoots

Postoperative pain control after cesarean delivery under spinal anesthesia is effectively obtained with morphine 0.1-0.3 mg intrathecally, although there may be dose-dependent side effects. We evaluated the quality of analgesia and the incidence of side effects with smaller doses of intrathecal morphine combined with intramuscular (i.m.) diclofenac. One hundred-twenty pregnant patients were allocated into six groups, which received the following treatments: Groups 1, 3, and 5 received 0.1, 0.05, and 0.025 mg of intrathecal morphine, respectively, plus 75 mg of i.m. diclofenac every 8 h; Groups 2, 4, and 6 received 0.1, 0.05, and 0.025 mg of intrathecal morphine, respectively, plus i.m. diclofenac on demand. Spinal anesthesia was performed with 15 mg of 0.5% hyperbaric bupivacaine. Pain scores and side effects were evaluated hourly for the first 24 h. Groups 1 and 2 had lower pain scores than Groups 3, 4, 5, and 6. However, only patients in Groups 2, 4, and 6 requested additional analgesics. Severe pruritus was more frequent in Groups 1 and 2. No patient experienced respiratory depression. We conclude that there is no advantage in using doses larger than 0.025 mg of intrathecal morphine if they are combined with systemic diclofenac. IMPLICATIONS: A multimodal approach to pain control may provide good quality analgesia while reducing drug-related side effects. In this study, a very small dose of intrathecal morphine, in association with intramuscular diclofenac, proved effective for controlling pain after cesarean delivery, with a low incidence of morphine-induced pruritus.     

Opioid-sparing effects of a low-dose infusion of naloxone in patient-administered morphine sulfate

BACKGROUND: A naloxone infusion is effective in reducing epidural and intrathecal opioid-related side effects. The use of naloxone infusion concomitant with intravenous morphine patient-controlled analgesia (PCA) has not been evaluated, probably because of an expected direct antagonism of the systemic opioid effect. The authors compared the incidence of morphine-related side effects and the quality of analgesia from two small doses of naloxone infusion. METHODS: Sixty patients classified as American Society of Anesthesiologists physical status 1, 2, or 3 who were scheduled for total abdominal hysterectomies were enrolled in the study. Patients received a standardized general anesthetic. In the postanesthetic care unit, patients received morphine as a PCA. They were randomized to receive either 0.25 microg x kg(-1) x h(-1) naloxone (low dose), 1 microg x kg(-1) x h(-1) (high dose), or saline (placebo) as a continuous infusion. Verbal rating scores for pain, nausea, vomiting, and pruritus; sedation scores; requests for antiemetic; and morphine use were recorded for 24 h. Blood pressure, respiratory rate, and oxyhemoglobin saturation were also monitored. RESULTS: Sixty patients completed the study. Both naloxone doses were equally effective in reducing the incidence of nausea, vomiting, and pruritus compared with placebo (P < 0.05 by the chi-squared test). There was no difference in the verbal rating scores for pain between the groups. The cumulative morphine use was the lowest in the low-dose group (42.3 +/- 24.1 mg; means +/- SD) compared with the placebo (59.1 +/- 27.4 mg) and high-dose groups (64.7 +/- 33.0 mg) at 24 h (P < 0.05 by analysis of variance). There was no incidence of respiratory depression (<8 breaths/min) and no difference in sedation scores, antiemetic use, respiratory rate, and hemodynamic parameters among the groups. CONCLUSIONS: Naloxone is effective in preventing PCA opioid-related side effects. Naloxone infusion at 0.25 microg x kg(-1) x h(-1) not only attenuates these side effects but appears to reduce postoperative (beyond 4-8 h) opioid requirements. This dosing regimen can be prepared with 400 microg naloxone in 1,000 ml crystalloid given in 24 h to a patient weighing 70 kg.     

A survey on the intended purposes and perceived utility of preoperative cardiology consultations

N-methyl-D-aspartate (NMDA) antagonists, such as MK801, delay the development of morphine tolerance. Magnesium, a noncompetitive NMDA antagonist, reduces postoperative morphine requirements. The present study was designed to evaluate the effects of intrathecal co-administration of magnesium sulfate with morphine on antinociceptive potentiation, tolerance, and naloxone-induced withdrawal signs. Magnesium sulfate (40-60 microg/h) co-administration for 7 days, similar to MK801 (10 nmol/h), prevented the decline in antinociceptive response compared with morphine (20 nmol/h). Magnesium sulfate (60 microg/h) produced no antinociception, but co-infused with morphine (1 nmol/h), it resulted in potentiated antinociception compared with morphine throughout the 7-day period. Probe morphine doses after 7-day infusions demonstrated a significantly greater 50% effective dose value for morphine 1 nmol/h (109.7 nmol) compared with saline (10.9 nmol), magnesium sulfate 60 microg/h (10.9 nmol), and magnesium sulfate 60 microg/h plus morphine 1 nmol/h (11.2 nmol), which indicates that magnesium had delayed morphine tolerance. Morphine withdrawal signs after naloxone administration were not altered by the co-infusion of magnesium sulfate. Cerebrospinal fluid magnesium levels after intrathecal magnesium sulfate (60 microg/h) for 2 days increased from 17.0 +/- 1.0 microg/mL to 41.4 +/- 23.6 microg/mL, although serum levels were unchanged. This study demonstrates antinociceptive potentiation and delay in the development of morphine tolerance by the intrathecal coinfusion of magnesium sulfate and morphine in the rat. Implications: The addition of magnesium sulfate, an N-methyl-D-aspartate antagonist, to morphine in an intrathecal infusion provided better analgesia than morphine alone in normal rats. These results suggest that intrathecal administration of magnesium sulfate may be a useful adjunct to spinal morphine analgesia.     

Decrease in isoflurane requirements and of postoperative pain with preanesthetic intrathecal morphine

OBJECTIVES: 1) To determine whether preanesthetic intrathecal administration of 0.5 mg morphine reduces isoflurane requirements for anesthetic maintenance. 2) To assess the duration of postoperative analgesia and the type and frequency of complications attributable to the procedure. PATIENTS AND METHODS: A series of 45 adults were distributed into 3 groups of 15 patients each based on site of surgery and site of preanesthetic (30 min) injection of 0.5 mg pure morphine. Control group (C0) patients underwent lumbar surgery and received subcutaneous morphine. Group C0.5 patients also underwent lumbar surgery but received intrathecal morphine. Group A0.5 patients underwent long-duration high abdominal surgery and received intrathecal morphine. Anesthesia was maintained with nitrous oxide (60%) in oxygen (40%) and a variable concentration of isoflurane. Isoflurane needs were assessed by averaging six consecutive measurements of end-tidal isoflurane pressure (M30FETiso) taken at intervals of 5 min. Postoperative analgesia was evaluated by means of a visual analog scale that was converted to numerical units (VASn). RESULTS: M30FETiso in group C0 (0.8%) was always higher (p < 0.01) than in the other two groups. M30FETiso in group A0.5 was higher (p < 0.01) than in group C0.5 during the first 150 min of surgery. After 180 min, there were no differences in M30FETiso (0.10-0.16%) between the two groups receiving intrathecal morphine. VASn results (mean +/- SD) in the first 4 hours were higher in group C0 (7.33 +/- 0.6) than in group C0.5 (1.13 +/- 0.35) and group A0.5 (1.07 +/- 0.26). The time of morphine-dependent analgesia was shorter (p < 0.01) in group C0 (0.62 +/- 0.38 hours) than in groups C0.5 (30.4 +/- 5.11 hours) and A0.5 (28 +/- 4.34 hours). There were no significant differences between the two groups receiving intrathecal morphine. CONCLUSIONS: Preanesthetic subarachnoid lumbar injection of 0.5 mg of pure morphine reduced early requirements for isoflurane in lumbar surgery (0.14% after 60 min). This reduction was initially less in patients undergoing abdominal surgery (0.44% at 60 min) but was the same after 150 min. Postoperative analgesia was long-term and independent of type or duration of surgery. There was no respiratory depression after surgery and the incidence of postoperative complications was similar in the two groups that received subarachnoid morphine.     

Drug-resistant tuberculosis in Singapore, 1995 to 1996

BACKGROUND: Thymectomy can induce a remission or at least an improvement in myasthenia gravis (MG) patients. After sternotomy MG patients with compromised muscle strength need an excellent postoperative pain relief. This study was designed to evaluate the efficacy of intrathecal morphine (ITM) on ventilatory function among MG patients undergoing trans-sternal thymectomy, when intravenous morphine served as control. METHODS: Twenty consecutive MG patients were randomised to receive either morphine (10 micrograms/kg) intrathecally at induction or intravenous morphine (30 micrograms/kg) with a patient-controlled analgesia (PCA) device. Anaesthesia was standardised. Forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1), respiratory rate, oxygen saturation, arterial blood gases, pain intensity and morphine consumption were assessed during 48 hours. RESULTS: The mean age of the patients was 35 +/- 3.4 years and the mean duration of the disease 1.9 +/- 0.5 years. According to Osserman's classification 70% of the patients belonged to Class IIA and 30% to Class IIB. ITM restored ventilatory function significantly better than iv PCA morphine. FVC recovered to 60% and FEV1 to 57% of the baseline values in the ITM group compared with 32% (P < 0.05) and 37% in the PCA morphine group, respectively. Postpuncture headache occurred in 4/10 patients. CONCLUSION: Intrathecal morphine provided effective postoperative analgesia and significantly improved ventilatory function when compared with intravenous morphine.     

A physiologic assessment of intrathecal amitriptyline in sheep

BACKGROUND: Intrathecal injection of amitriptyline enhances antinociception from intravenous morphine and reduces neuropathic pain behavior in animals. This study represents part of a preclinical assessment of intrathecal amitriptyline to determine its safety for use in humans. METHODS: Low thoracic intrathecal, femoral, and pulmonary arterial catheters were inserted in 18 adult ewes, followed 96 h later by intrathecal injection of saline or 5 mg amitriptyline and by determination of spinal cord blood flow, hemodynamic variables, behavioral changes, cerebrospinal fluid concentrations of catecholamines and amitriptyline, and spinal tissue concentrations of amitriptyline. In six other ewes, low thoracic intrathecal and femoral arterial catheters were inserted and blood pressure and heart rate were measured after intrathecal injection of saline or 0.25, 1, or 5 mg amitriptyline. Four other ewes received cervical intrathecal injection of 5 and 10 mg amitriptyline, and antinociception was determined. RESULTS: Thoracic intrathecal injection of amitriptyline produced dose-dependent sedation but did not significantly affect spinal cord blood flow or hemodynamic variables. Spinal cord tissue concentrations of amitriptyline were 100 times greater in tissue near the tip of the thoracic intrathecal catheter compared with cervical cord tissue. Cerebrospinal fluid concentrations of catecholamines did not significantly change after amitriptyline was administered. Cervical intrathecal injection of 5 mg amitriptyline produced mild antinociception, whereas 10 mg produced intense sedation and, in one sheep, seizures and death. CONCLUSIONS: Although other preclinical toxicity studies are necessary before introducing intrathecal amitriptyline for use in humans, this study did not reveal dangerous changes in blood pressure or spinal cord blood flow from this agent.     

Dose-response relationship of intrathecal morphine for postcesarean analgesia

BACKGROUND: This series investigated the quality of analgesia and the incidence and severity of side effects of intrathecal morphine for post-cesarean analgesia administered over a dose range of 0.0-0.5 mg. METHODS: ONE hundred eight term parturients undergoing cesarean delivery at term and given spinal anesthesia were randomized to receive a single dose of intrathecal morphine (0.0, 0.025, 0.05, 0.075, 0.1, 0.2, 0.3, 0.4, or 0.5 mg). A patient-controlled analgesia (PCA) device provided free access to additional analgesics. PCA morphine use, incidence and severity of side effects, and need for treatment interventions were recorded for 24 h. Data were analyzed with analysis of variance and linear regression analysis for trends among groups. RESULTS: Patient-controlled analgesia use differed significantly between groups; PCA use was higher in the control group than in groups receiving 0.075, 0.1, 0.3, 0.4, or 0.5 mg. Twenty-four-hour PCA morphine use was 45.7 mg lower (95% CI, 4.8-86.6 mg lower) in the 0.075-mg group than the control group. There was no difference in PCA morphine use between the 0.075- and 0.5-mg groups (95% CI, 36.8 mg lower to 45.0 mg higher); despite a fivefold increase in intrathecal morphine dose, PCA morphine use remained constant. There was no difference between control and treatment groups or among treatment groups with respect to nausea and vomiting. Pruritus and the need for treatment interventions increased in direct proportion to the dose of intrathecal morphine (linear regression, P = 0.001 and P = 0.0002, respectively). CONCLUSIONS: These data indicate there is little justification for use of more than 0.1 mg for post-cesarean analgesia. For optimal analgesia, augmentation [corrected] of intrathecal morphine with systemic opioids may be necessary.     

Long-term effects of continuous intrathecal opioid treatment in chronic pain of nonmalignant etiology

In the present retrospective investigation, the long-term effects of continuous intrathecal opioid therapy via implantable infusion pump systems were examined in 120 patients with chronic, nonmalignant pain syndromes. The follow-up period was 6 months to 5.7 years (mean 3.4 years +/- 1.3 standard error of the mean). Deafferentation pain and neuropathic pain showed the best long-term results, with 68% and 62% pain reduction (visual analog scale), respectively. The mean morphine dosage initially administered was 2.7 mg/day (range 0.3-12 mg/day); after an average of 3.4 years, it was 4.7 mg/day (range 0.3-12 mg/day). In a long-term observation of 28 patients who received intrathecal morphine for longer than 4 years. 18 patients (64.3%) had a constant dosage history and 10 patients (35.7%) showed an increase in morphine dosage to more than 6 mg/day 1 year after dosage determination. In seven cases, a tolerance developed: in four patients the tolerance was controlled by means of "drug holidays"; but in three patients it was necessary to remove the pump systems. Explantation of the pump system occurred in 22 additional cases for other reasons. Throughout the follow-up period, 74.2% of the patients profited from the intrathecal opiate therapy: the average pain reduction after 6 months was 67.4% and, as of the last follow-up examination, it was 58.1%. Ninety-two percent of the patients were satisfied with the therapy and 81% reported an improvement in their quality of life. The authors' 6-year experience with administration of intrathecal opioid medications for nonmalignant pain should encourage the use of this method in carefully selected patients.     

Determination of an effective dose of intrathecal morphine for pain relief after cesarean delivery

Very small doses of intrathecal (i.t.) morphine (25-200 microg) have been used in an effort to provide effective postoperative pain relief while minimizing side effects after cesarean delivery. We performed a double-blinded study in 40 patients presenting for elective cesarean delivery in which i.t. morphine was administered along with oral hydrocodone/acetaminophen and other medications commonly administered after cesarean delivery. We administered i.t. morphine by up-down sequential allocation of doses. For the purposes of this study, adequate postoperative analgesia was defined as comfort not requiring i.v. morphine for 12 h after spinal anesthesia with bupivacaine, fentanyl, and morphine. In addition, a time and cost comparison was performed for study patients receiving intrathecal morphine compared with a historical group of patients receiving patient-controlled analgesia with i.v. morphine. We were unable to determine with meaningful precision a dose of i.t. morphine to provide analgesia in this context. However, very small doses of i.t. morphine combined with oral hydrocodone/acetaminophen and other medications commonly prescribed after cesarean delivery provided postoperative pain relief with no more time commitment than patient-controlled analgesia (148 +/- 61 vs 150 +/- 57 min) and with significantly less acquisition cost ($15.13 +/- $4.40 vs $34.64 +/- $15.55). Implications: When used along with oral analgesics, very small doses of spinal morphine provide adequate pain relief after cesarean delivery. Spinal anesthetics, oral analgesics, and other medications commonly prescribed to treat side effects after cesarean delivery contribute significantly to this analgesia. When small doses of spinal morphine are used in this setting, they provide adequate analgesia and patient satisfaction that is time- and cost-effective.     

Postoperative analgesia after co-administration of clonidine and morphine by the intrathecal route in patients undergoing hip replacement

Postoperative analgesia after intrathecal co-administration of clonidine hydrochloride (75 micrograms) and morphine sulfate (0.5 mg) was compared with analgesia produced after either intrathecal morphine (0.5 mg) or 0.9% sodium chloride in 90 patients undergoing total hip replacement under bupivacaine spinal anesthesia. Patient-controlled morphine requirements were significantly reduced (P < 0.001) postoperation by both clonidine/morphine (median 5 mg/24 h) and morphine (median 7 mg/24 h) compared with control (saline) (median 28 mg/24 h). However, no significant additional reduction in postoperative analgesic requirements was shown with the clonidine/morphine combination compared with morphine alone. Visual analog pain scores, although good in all groups at all times, were significantly poorer in the control group at 2 h (P < 0.04) and 4 h (P < 0.001) after operation compared with both treatment groups, and significantly poorer than the clonidine/morphine group at 6 h (P < 0.002) and 24 h (P < 0.009) postoperation. Mean arterial blood pressure was significantly lower in the clonidine/morphine group than in the two other groups (P < 0.001) between 2 and 5 h after operation. The incidence of emesis was similar in the clonidine/morphine and morphine groups and was significantly more than in the control group.     

Extent and severity of periodontal destruction based on partial clinical assessments

OBJECTIVES: To evaluate the postoperative analgesic efficacy, side effects and acceptance by patients and nurses of intravenous "patient-controlled analgesia" (PCA) with morphine, metamizole and buprenorphine. MATERIAL AND METHODS: In this randomized double blind prospective study of 150 patients in three groups receiving morphine (group A), metamizole (group B) or buprenorphine (group C), the patients had undergone low abdominal surgery with the same anesthetic protocol. Pain was recorded during the first 48 h after surgery on an orally-communicated scale of none or slight = 0, moderate = 1 and severe = 2. Upon the first report of moderate pain, patients were administered an intravenous bolus containing 5 mg morphine, 1 g metamizole or 0.15 mg buprenorphine. A perfusion pump was then connected and set with one bolus of 1.2 mg morphine, one of 333 mg metamizole or one of 0.04 buprenorphine. The maximum dose allowed in 24 h was 40 mg morphine, 8 g metamizole or 1.2 mg buprenorphine. The minimum interval between doses was 30 min for all three groups. Side effects reported were respiratory depression, sedation, nausea, vomiting, pruritus, perspiration and pain upon administration. Patients and nurses were asked to evaluate the system when the pump was disconnected and the results were then analyzed statistically. RESULTS: The analgesic effect was satisfactory in all three groups, with no significant differences among them. The percentages of patients reaching the maximum allowed dose on the first day were 2% with morphine, 18% (p < 0.05) with metamizole and 8% with buprenorphine. No respiratory depression was observed. Sedation was greater with morphine and buprenorphine than with metamizole (p = 0.0001). Pruritus was also greater with morphine and buprenorphine than with metamizole (p = 0.02) and pain upon infusion was greater with metamizole (p = 0.0002). CONCLUSIONS: Intravenous postoperative PCA was effective with all three drugs studied. Patient and nurse acceptance was good and side effects were few in the three groups. The lower rate of side effects for metamizole makes it the drug of choice.     

Interaction of intrathecally infused morphine and lidocaine in rats (part II): effects on the development of tolerance to morphine

BACKGROUND: There has been little information regarding the effects of local anesthetics on tolerance to opioids, although chronic use of combination of opioids and local anesthetics is popular for pain control. This study was designed to examine the effects of lidocaine on morphine tolerance to somatic and visceral antinociception. METHODS: Rats received a continuous intrathecal infusion of morphine (0.3-10 microg x kg(-1) x h(-1)), lidocaine (30-1000 microg x kg(-1). h(-1)), a combination of those, or saline. After 6- day infusion, intrathecal morphine challenge test (5 microg/10 microl) was performed, and time-response curve was constructed to assess the magnitude of tolerance. The tail flick (TF) test and colorectal distension (CD) test were used to measure somatic and visceral antinociceptive effects, respectively. RESULTS: Antinociceptive effects in the TF and CD tests caused by morphine challenge were reduced (P < 0.01) in the morphine infused groups. The magnitude of the tolerance was inversely associated with the amount of morphine infused. Lidocaine infusion induced no different change in the morphine challenge test from that seen in the saline infusion group. Development of tolerance was greater in morphine 3 microg x kg(-1) h(-1) than in morphine 0.75 microg x kg(-1) x h(-1) + lidocaine 150 microg x kg(-1) x h(-1) despite their similar antinociceptive effects during intrathecal infusion. The infusion of a low dose of morphine (0.3 microg kg(-1) x h(-1)) did not reduce the antinociceptive effects in the challenge test. CONCLUSION: Lidocaine in combination with morphine does not reduce tolerance to morphine nor develop cross-tolerance. The intrathecal infusion of morphine induced tolerance to somatic and visceral antinociception in a dose-dependent fashion.     

A prospective study of long-term intrathecal morphine in the management of chronic nonmalignant pain

OBJECTIVE: To examine in a prospective manner the long-term safety and efficacy of chronic intrathecal morphine in patients with severe, nonmalignant pain refractory to less invasive modalities. METHODS: Forty patients with severe, chronic nonmalignant pain poorly managed by systemic medications were identified as candidates for intraspinal trial of morphine. Thirty participants reported successful pain relief during trial and were implanted with an intraspinal delivery system. Standardized measures of pain and functional status were assessed before treatment was begun and at defined intervals during the subsequent 24 months. Intrathecal opioid use and pharmacological and device-related complications were also monitored. RESULTS: The participants had a mean age of 58 +/- 13 years and a mean pain duration of 8 +/- 9 years. Fifty-three percent of the study participants were women. Pain type was characterized as mixed neuropathic-nociceptive (15 of 30 patients, 50%), peripheral neuropathic (10 of 30 patients, 33%), deafferentation (4 of 30 patients, 13%), or nociceptive (1 of 30 patients, 3%). Forty-seven percent of the patients were diagnosed with failed back surgery syndrome. Significant improvement over baseline levels of visual analog scale pain was measured at each follow-up examination after implant. Overall, 50% (11 of 22 patients) of the population reported at least a 25% reduction in visual analog scale pain after 24 months of treatment. In addition, the McGill Pain Questionnaire, visual analog scale measures of functional improvement and pain coping, and several subscales of the Chronic Illness Problem Inventory showed improvement throughout the follow-up period. Pharmacological side effects were managed medically by morphine dose reduction, addition of bupivacaine, or replacement of morphine with hydromorphone. Device-related complications requiring repeat operations were experienced by 20% of the patients. CONCLUSION: Continuous intrathecal morphine can be a safe, effective therapy for the management of severe, nonmalignant pain among a carefully selected patient population and can result in long-term improvement in several areas of daily function.     

Effects of systemic, intracerebral, or intrathecal administration on an N-methyl-D-aspartate receptor antagonist on associative morphine analgesic tolerance and hyperalgesia in rats.

A flavor paired with morphine shifted to the right the function relating morphine dose to tail-flick latencies and provoked hyperalgesic responses when rats were tested in the absence of morphine. These learned increases in nociceptive sensitivity were not mediated by alterations in tail-skin temperature. Microinjection of the competitive N-methyl-D-aspartate (NMDA) receptor antagonist D,L-2-amino-5-phosphonopentanoic acid (AP-5) into the lateral ventricle reversed the hyperalgesic responses but spared the tolerance to morphine analgesia. By contrast, systemic administration of the noncompetitive NMDA receptor antagonist MK-801 or intrathecal infusion of AP-5 reversed the hyperalgesic responses as well as the tolerance to morphine analgesia. The results demonstrate that associatively mediated tolerance to morphine analgesia can co-occur with hyperalgesic responses and are discussed relative to learned activation of endogenous pronociceptive mechanisms. (PsycINFO Database Record (c) 2010 APA, all rights reserved)