Continuous Intrathecal Morphine Infusion Research Articles

Cost-Effectiveness and Cost–Utility Analyses in Thailand of Continuous Intrathecal Morphine Infusion Compared with Conventional Therapy in Cancer Pain: A 10-year Multicenter Retrospective Study

ABSTRACT Background Because of the high initial cost of intrathecal drug delivery (ITDD) therapy, this study investigated the cost-effectiveness and cost–utility of ITDD therapy in refractory cancer pain management in Thailand over the past 10 years. Methods The retrospective study was conducted in patients with cancer pain who underwent ITDD therapy from January 2011 to 2021 at three university hospitals. Clinical outcomes included the numerical rating scale (NRS), Palliative Performance Scale, and the EQ-5D. The direct medical and nonmedical as well as indirect costs were also recorded. Cost-effectiveness and cost–utility analyses were performed comparing ITDD therapy with conventional therapy (extrapolated from costs of the same patient before ITDD therapy) from a societally oriented economic evaluation. Results Twenty patients (F:M: 10:10) aged 60 ± 15 years who underwent implantation of an intrathecal percutaneous port (IT port; n = 15) or programmable intrathecal pump (IT pump; n = 5) were included. The median survival time was 78 (interquartile range = 121–54) days after ITDD therapy. At 2-month follow-up, the incremental cost-effectiveness ratio (ICER)/pain reduction of an IT port (US$2065.36 (CA$2829.54)/2-point NRS reduction/lifetime) was lower than for patients with an IT pump (US$5479.26 (CA$7506.58)/2-point NRS reduction/lifetime) compared with continued conventional therapy. The ICER/quality-adjusted life years (QALYs) gained for an IT port compared with conventional treatment was US$93,999.31(CA$128,799.06)/QALY gained, which is above the cost-effectiveness threshold for Thailand. Conclusion The cost-effectiveness and cost–utility of IT port therapy for cancer pain was high relative to the cost of living in Thailand, above the cost-effectiveness threshold. Prospective cost analysis studies enrolling more patients with diverse cancers that investigate the benefit of early ITDD therapy with devices over a range of prices are warranted.

Characterization of Effect of Repeated Bolus or Continuous Intrathecal Infusion of Morphine on Spinal Mass Formation in the Dog

We determined whether intrathecally delivering the same daily dose of morphine (MS) at a fixed concentration of 25 mg/mL by periodic boluses versus continuous infusion would reduce intrathecal mass (IMs) formation in dogs. Adult dogs (hound cross, n = 32) were implanted with intrathecal catheters connected to SynchroMed II infusion pumps. Animals were randomly assigned to receive infusion of 0.48 mL/day of saline or MS dosing (12 mg/day at 25 mg/mL) as boluses: x1 (q24hour), x2 (q12hour), x4 (q6hour), or x8 (q3hour) given at the rate of 1000 μL/hour, or as a continuous infusion (25 mg/mL/20 μL/hour). With IT saline, minimal pathology was noted. In contrast, animals receiving morphine displayed spinally compressing durally derived masses with the maximal cross-sectional area being greatest near the catheter tip. Histopathology showed that IMs consisted of fibroblasts in a collagen (type 1) matrix comprised of newly formed collagen near the catheter and mature collagen on the periphery of the mass. The rank order of median cross-sectional mass area (mm2 ) was: Saline: 0.7 mm2 ; x2: 1.8 mm2 ; x4: 2.7 mm2 ; x1: 2.7 mm2 ; x8: 4.2 mm2 ; Continuous: 8.1 mm2 , with statistical difference from saline being seen with continuous (p < 0.0001) and x8 (p < 0.05). Bench studies with a 2D diffusion chamber confirmed an increase in dye distribution and lower peak concentrations after bolus delivery versus continuous infusion of dye. Using multiple bolus dosing, IMs were reduced as compared to continuous infusion, suggesting relevance of bolus delivery in yielding reduced intrathecal masses.

445 Continuous Intrathecal Morphine Infusion for Pain Management in a Patient with Burn Injury

445 Continuous Intrathecal Morphine Infusion for Pain Management in a Patient with Burn Injury

Spinal Myoclonus Responding to Continuous Intrathecal Morphine Pump.

Spinal myoclonus is a sudden, brief, and involuntary movement of segmental or propriospinal muscle groups. Spinal myoclonus has occasionally been reported in patients undergoing opioid therapy, but the pathophysiology of opioid-induced myoclonus has not been elucidated yet. Here, we present two patients with spinal segmental myoclonus secondary to ischemic and radiation myelopathy. Conventional medications did not help treat persistent myoclonus in both legs. Continuous intrathecal morphine infusion was implanted for pain control in one patient, which relieved spinal myoclonus entirely. This experience led to the application of this method with a second patient, leading to the same gratifying result. Spinal myoclonus reemerged as soon as the morphine pumps were off, which confirmed the therapeutic role of opioids. In contrast to the opioid-induced myoclonus, these cases show a benefit of opioids on spinal myoclonus, which could be explained by synaptic reorganization after pathologic insults in the spinal cord.

CXCL12/CXCR4 Signaling Contributes to the Pathogenesis of Opioid Tolerance: A Translational Study.

Long-term opioid therapy for chronic pain may lead to analgesic tolerance, especially when administered intrathecally, thus preventing adequate pain relief. Discovering drug targets to treat opioid tolerance using a mechanism-based approach targeting opioid-induced neuroinflammation provides new therapeutic opportunities. In this study, we provide translational evidence that CXCL12/CXCR4 signaling contributes to the pathogenesis of opioid tolerance. The CXCL12 levels in the cerebrospinal fluid of opioid-tolerant patients were compared with those of opioid-naive subjects. For further investigation, a rodent translational study was designed using 2 clinically relevant opioid delivery paradigms: daily intraperitoneal morphine injections and continuous intrathecal morphine infusion. We measured rats' tail flick responses and calculated the percentage of maximum possible effects (%MPE) to demonstrate opioid acute antinociception and the development of analgesic tolerance. The effects of exogenous CXCL12, CXCL12 neutralizing antibody, and receptor antagonist AMD3100 were investigated by intrathecal administration. Data were presented as mean ± SEM. CXCL12 was significantly upregulated in the cerebrospinal fluid of opioid-tolerant patients for 892 ± 34 pg/mL (n = 27) versus 755 ± 33 pg/mL (n = 10) in naive control subjects (P = .03). Furthermore, after 2 and 5 days of intrathecal morphine infusion, rat lumbar spinal cord dorsal horn CXCL12 messenger RNA levels were significantly upregulated by 3.2 ± 0.7 (P = .016) and 3.4 ± 0.3 (P = .003) fold, respectively. Results from the daily intraperitoneal morphine injection experiments revealed that administering an intrathecal infusion of CXCL12 for 24 hours before the first morphine injection did not decrease antinociception efficacy on day 1 but accelerated tolerance after day 2 (%MPE 49.5% vs 88.1%, P = .0003). In the intrathecal morphine coinfusion experiments, CXCL12 accelerated tolerance development (%MPE 9.4% vs 43.4% on day 1, P < .0001), whereas coadministration with CXCL12 neutralizing antibody attenuated tolerance (72.5% vs 43.4% on day 1, P < .0001; 47.6% vs 17.5% on day 2, P < .0001). Coadministration of receptor antagonist AMD 3100 can persistently preserve morphine analgesic effects throughout the study period (27.9% ± 4.1% vs 0.9% ± 1.6% on day 5, P = .03). The CXCL12/CXCR4 pathway contributes to the pathogenesis of opioid tolerance. Our study indicates that intervening with CXCL12/CXCR4 signaling has therapeutic potential for opioid tolerance.

Intrathecal rapamycin attenuates morphine-induced analgesic tolerance and hyperalgesia in rats with neuropathic pain

Repeated and long-term administration of opioids is often accompanied by the initiation of opioid-induced analgesic tolerance and hyperalgesia in chronic pain patients. Our previous studies showed that repeated intrathecal morphine injection activated the mammalian target of rapamycin complex 1 (mTORC1) in spinal dorsal horn neurons and that blocking this activation prevented the initiation of morphine-induced tolerance and hyperalgesia in healthy rats. However, whether spinal mTORC1 is required for morphine-induced tolerance and hyperalgesia under neuropathic pain conditions remains elusive. We here observed the effect of intrathecal infusion of rapamycin, a specific mTORC1 inhibitor, on morphine-induced tolerance and hyperalgesia in a neuropathic pain model in rats induced by the fifth lumbar spinal nerve ligation (SNL). Continuous intrathecal infusion of morphine for one week starting on day 8 post-SNL led to morphine tolerance demonstrated by morphine-induced reduction in maximal possible analgesic effect (MPAE) to tail heat stimuli and ipsilateral paw withdrawal threshold (PWT) to mechanical stimuli in SNL rats. Such reduction was attenuated by co-infusion of rapamycin. Co-infusion of rapamycin also blocked morphine tolerance demonstrated by attenuation of morphine-induced reduction in MPAE in sham rats and morphine-induced hyperalgesia demonstrated by the reverse of morphine-induced reduction in PWT on both sides of sham rats and on the contralateral side of SNL rats. The results suggest that mTORC1 inhibitors could serve as promising medications for use as adjuvants with opioids in clinical neuropathic pain management.

Persistent Hiccups With Continuous Intrathecal Morphine Infusion

To report a case of hiccups secondary to intrathecal (IT) morphine infusion. Case report and discussion. The hiccups in our patient resolved on substitution of IT morphine infusion with hydromorphone. We report a case of a 44-year-old man who developed persistent hiccups with IT morphine infusion pump therapy. The hiccups persisted despite various nonpharmacological and pharmacological measures. The untoward symptom resolved after substitution of IT hydromorphone for IT morphine.

Antinociceptive potentiation and attenuation of tolerance by intrathecal β-arrestin 2 small interfering RNA in rats

Tolerance to the analgesic effect of opioids complicates the management of persistent pain states. We tested whether the intrathecal infusion of small interfering RNA (siRNA) against β-arrestin 2 would reduce tolerance to chronic morphine use and the severity of precipitated morphine withdrawal. Intrathecal β-arrestin 2 (2 μg siRNA per 10 μl per rat) was injected once daily for 3 days. Rats then received a continuous intrathecal infusion of morphine (2 nmol h⁻¹) or saline for 7 days. Daily tail-flick (TF) and intrathecal morphine challenge tests were performed to assess the effect of intrathecal β-arrestin 2 siRNA on antinociception and tolerance to morphine. Naloxone withdrawal (2 mg kg⁻¹) was performed to assess morphine dependence. In the daily TF test, the antinociception of intrathecal morphine was increased and maintained in rats receiving β-arrestin 2 siRNA compared with the control group (morphine alone). In the probe response test, rats receiving morphine infusion with β-arrestin 2 siRNA treatment showed a significant left shift in their dose-response curve, as measured by per cent maximal possible effect (MPE), such that the AD₅₀ was significantly decreased by a factor of 5.6 when compared with that of morphine-infused rats. In the naloxone-induced withdrawal tests, rats receiving β-arrestin 2 siRNA injection with morphine infusion showed a significant reduction in four of the six signs of withdrawal. We show here that intrathecal β-arrestin 2 siRNA in rats enhances analgesia and attenuates naloxone-induced withdrawal symptoms. This may warrant further investigation in the context of long-term use of intrathecal opioids for controlling chronic pain.

Paravertebral Cervical Nerve Block in a Patient Suffering from a Pancoast Tumor

In patients with aggressive tumors resistant to conventional pain treatment, regional anaesthesia frequently becomes an alternative therapy. Cervical paravertebral nerve block among several access options to the brachial plexus is barely ever used. We present a case with severe shoulder and upper extremity pain owing to an expanding Pancoast tumor exhibiting compression upon the brachial plexus. Continuous intrathecal morphine infusion and adjuvant treatment was not sufficient to render the patient pain-free. With the addition of paravertebral nerve blockade the patient's pain improved substantially, however without impacting his longevity.

Continuous Intrathecal Morphine Infusion in Patients With Vertebral Fractures Due to Osteoporosis

Vertebral fractures are the most common consequences of severe osteoporosis. The chronic pain from collapse of osteoporotic vertebrae affects quality of life (QOL) and autonomy of patients. The management of pain with oral or transdermal opiates can cause severe side effects. Continuous intrathecal administration of morphine via an implantable pump might represent an alternative therapy to conventional oral or transdermal administration of opioids and has some advantages and disadvantages for pain relief and improvement in QOL when compared with conventional opioid delivery. It is our objective to report our experience using intrathecal delivery of analgesics in a population of patients with refractory pain due to vertebral fractures. In 24 patients, refractory to conventional delivery of opioids, we used intrathecal analgesic therapy. To test for efficacy and improvement in QOL, we administered the visual analog scale for pain and the Questionnaire of the European Foundation of Osteoporosis (QUALEFFO). Before patients were selected for pump implantation, an intraspinal drug delivery trial was performed to monitor side effects and responses to intrathecal therapy. Significant pain relief was obtained in all implanted patients. Using the QUALEFFO, we observed significant improvement of all variables such as quality of daily life, domestic work, ambulation, and perception of health status, before and after 1 year after pump implantation. With intrathecal morphine infusion, none of the 24 patients required additional systemic analgesic medication. The mean morphine dose during the spinal trial was 11.28 mg/d, 7.92 mg/d at pump implantation, and 16.32 mg/d at 1-year follow-up. Our results show that intrathecal administration of morphine efficiently relieves the symptoms of pain and improves QOL. Continuous intrathecal administration of morphine appears to be an alternative therapy to conventional analgesic drug delivery and has advantages in those patients who have severe side effects with systemic administration of analgesics.

The Management of Pain From Collapse of Osteoporotic Vertebrae With Continuous Intrathecal Morphine Infusion

Objectives. Vertebral fractures are the most common consequences of severe osteoporosis. The chronic pain from collapse of osteoporotic vertebrae affects quality of life (QoL) and autonomy of patients. The management of pain with oral or transdermal opiates can cause severe side-effects. Continuous intrathecal administration of morphine through an implantable pump might represent an alternative therapy to conventional oral or transdermal administration of opioids and has some advantages and disadvantages for pain relief and improvement in QoL when compared to conventional opioid delivery. It is our objective to report our experience using intrathecal delivery of analgesics in a population of patients with refractory pain due to vertebral fractures. Materials and Methods. In 24 patients, refractory to conventional delivery of opioids, we used intrathecal analgesic therapy. To test for efficacy and improvement in QoL, we administered the visual analog scale (VAS) for pain and the Quality of Life Questionnaire of the European Foundation for Osteoporosis (QUALEFFO). Before patients were selected for pump implantation, an intraspinal drug delivery trial was performed to monitor side-effects and responses to intrathecal therapy. Results. Significant pain relief was obtained in all implanted patients. Using the QUALEFFO, we observed significant improvement of all variables such as QDL (quality of daily life), DW (domestic work), ambulation, and PHS (perception of health status), before and after oneyear after pump implantation. With intrathecal morphine infusion, none of the 24 patients required additional systemic analgesic medication. The mean morphine dose during the spinal trial was 11.28mg/day, 7.92mg/day at pump implantation, and 16.32mg/day at one-year follow-up. Conclusions. Our results show that intrathecal administration of morphine efficiently relieves the symptoms of pain and improves QoL. Continuous intrathecal administration of morphine appears to be an alternative therapy to conventional analgesic drug delivery and has advantages in those patients who have severe side-effects with systemic administration of analgesics.

Time Course and Role of Morphine Dose and Concentration in Intrathecal Granuloma Formation in Dogs

Intrathecal morphine infusion leads to intrathecal granulomas. In dogs, the authors examined time course of granuloma formation and the role of concentration in granuloma development. Dogs were prepared with lumbar intrathecal catheters and vest-mounted pumps. To define the time course of granuloma formation, serial magnetic resonance imaging was performed in animals receiving 10 or 31 days of morphine infusion (12.5 mg/ml at 40 microl/h). At these times, morphine was removed from the infusate, and further magnetic resonance images were acquired over 14-35 additional days. To assess dose versus concentration, dogs received 28-day infusions of vehicle, 12 mg morphine/day as 12.5 mg/ml at 40 microl/h, or 1.5 mg/ml at 334 microl/h (12 mg/day) for 28 days. Additional dogs received 3 mg/day as 12.5 mg/ml at 10 mul/h. Serial magnetic resonance images in dogs receiving morphine (12.5 mg/ml at 40 microl/h) revealed pericatheter-enhancing tissues as early as 3 days with a prominent signal by 10 days. Removal of morphine reduced the mass volume within 7 days. At a fixed infusion rate, the incidence of granuloma formation with the continuous intrathecal infusion of morphine ranged from 0 in vehicle-treated dogs to 100% in dogs treated with 12.5 mg/ml at 40 microl/h (12 mg/day). Infusion of 12 mg/day at 1.5 mg/ml (334 microl/h) resulted in granuloma in one of four animals. The authors found that infusion of morphine in different concentrations at a fixed rate resulted in a dose-dependent increase in concentration, with the granuloma-producing, dose-yielding lumbar cerebrospinal fluid morphine concentrations around 40 microg/ml. Serial magnetic resonance imaging showed a rapid formation and regression of the masses initiated by intrathecal morphine infusion. These masses are dependent on local concentration.

Facilitation of spinal morphine analgesia in normal and morphine tolerant animals by neuropeptide SF and related peptides

Neuropeptide FF and related synthetic amidated peptides have been shown to elicit sustained anti-nociceptive responses and potently augment spinal anti-nociceptive actions of spinal morphine in tests of thermal and mechanical nociception. Recent studies have described the occurrence of another octapeptide, neuropeptide SF (NPSF) in the spinal cord and the cerebrospinal fluid and demonstrated its affinity for the NPFF receptors. This study examined the effects of NPSF and two putative precursor peptides, EFW-NPSF and NPAF, on the spinal actions of morphine in normal and opioid tolerant rats using the tailflick and pawpressure tests. In normal rats, NPSF demonstrated weak intrinsic activity but sub-effective doses of the peptide significantly increased the magnitude and duration of spinal morphine anti-nociception in both tests. A low-dose of NPSF also augmented the spinal actions of a delta receptor agonist, deltorphin. The morphine-potentiating effect of NPSF was shared by EFW-NPSF and the octadecapeptide NPAF. In animal rendered tolerant by continuous intrathecal infusion of morphine for 6 days, low dose NPSF itself elicited a significant anti-nociceptive response and potently increased morphine-induced response in both tests. In animals made tolerant by repeated injections of intrathecal morphine, administration of NPSF, EFW-NPSF, and NPAF with morphine reversed the loss of the anti-nociceptive effect and restored the agonist potency. The results demonstrate that in normal animals NPSF and related peptides exert strong potentiating effect on morphine anti-nociception at the spinal level and in tolerant animals these agents can reverse the loss of morphine potency.

Antinociceptive potentiation and attenuation of tolerance by intrathecal electric stimulation in rats.

We tested whether intrathecal electric stimulation would reduce the tolerance to chronic morphine use and the severity of precipitated morphine withdrawal. Rats received intrathecal electrode catheter implantation and a continuous intrathecal infusion of morphine (2 nmol/h) or saline for 7 days. Intrathecal electric stimulations (0, 20, or 200 V) were performed once daily during the same period. Daily tail-flick and intrathecal morphine challenge tests were performed to assess the effect of intrathecal electric stimulation on antinociception and tolerance to morphine. Naloxone withdrawal (2 mg/kg) was performed to assess morphine dependence, and changes in spinal neurotransmitters were monitored by microdialysis. The antinociceptive effect of intrathecal morphine was increased by 200 V of electric stimulation. The magnitude of tolerance was decreased in the rats receiving the 2 nmol/h infusion with 200 V of intrathecal electric stimulation compared with the control group (morphine 2 nmol/h alone) (AD(50), 13.6 vs 124.7 nmol). The severity of naloxone-induced withdrawal was less in the rats receiving 200 V of stimulation. Intrathecal stimulation thus enhances analgesia and attenuates naloxone-induced withdrawal symptoms in rats receiving chronic intrathecal morphine infusion. Increases in spinal glycine release may be the underlying mechanism. This method may merit further investigation in the context of the long-term use of intrathecal opioids for controlling chronic pain. Control of chronic pain is a major health problem. We show here that direct electrical stimulation of the spinal cord in rats enhances analgesia and attenuates naloxone-induced withdrawal symptoms. This may warrant further investigation in the context of long-term use of intrathecal opioids for controlling chronic pain.

Modulation of peripheral endogenous opioid analgesia by central afferent blockade.

Peripheral tissue injury causes a migration of opioid peptide-containing immune cells to the inflamed site. The subsequent release and action of these peptides on opioid receptors localized on peripheral sensory nerve terminals causes endogenous analgesia. The spinal application of opioid drugs blocks the transmission of nociceptive information from peripheral injury. This study investigates the influence of exogenous spinal opioid analgesia on peripheral endogenous opioid analgesia. Six and forty-eight hours after initiation of continuous intrathecal morphine infusion and administration of Freund's complete adjuvant into the hind paw of rats, antinociceptive and antiinflammatory effects were measured by paw pressure threshold, paw volume, and paw temperature, respectively. Inflammation and quantity of opioid-containing cells were evaluated by immunocytochemistry and flow cytometry. Cold water swim stress-induced endogenous analgesia was examined 24 h after discontinuation of intrathecal morphine administration. Intrathecal morphine (10 micro g/h) resulted in a significant and stable increase of paw pressure threshold ( P< 0.05) without changing inflammation, as evaluated by paw volume, paw temperature, and flow cytometry ( P> 0.05). At 48 but not at 6 h after Freund's complete adjuvant, the number of beta-endorphin-containing cells and cold water swim-induced antinociception were significantly reduced in intrathecal morphine-treated rats compared with those treated with intrathecal vehicle ( P< 0.05). These findings suggest an interplay of central and peripheral mechanisms of pain control. An effective central inhibition of pain apparently signals a reduced need for recruitment of opioid-containing immune cells to injured sites.

Continuous intrathecal morphine treatment for chronic pain of nonmalignant etiology: long-term benefits and efficacy

BACKGROUND To analyze, prospectively, the long-term effects of continuous intrathecal morphine infusion therapy in 16 patients with chronic nonmalignant pain syndromes. METHODS Twenty-five patients with severe, chronic, nonmalignant pain that had proven refractory to conservative management were considered candidates for trial of intrathecal spinal morphine. Sixteen patients achieved more than 50% pain relief after a trial period of intrathecal morphine infusion. They were implanted with fully implantable and programmable pumps through which morphine was delivered intrathecally on a continuous basis. These patients were followed prospectively and underwent careful evaluation of their functional and mental status, and pain intensity measurements using standardized techniques before treatment and every 6 months thereafter in the follow-up period. The follow-up period ranged from 13 months to 49 months (mean 29.14 months ± 12.44 months) for the patients who had implanted morphine pumps. RESULTS The mean morphine dosage initially administered was 1.11 mg/day (range 0.2–6.5 mg/day); after 6 months, it was 3.1 mg/day (range 0.4–8.75 mg/day). In long-term observation, no patient had a constant dosage history. The patients who received intrathecal morphine for longer than 2 years all showed an increase in morphine dosage to more than 10 mg/day. The best long-term results were seen with deafferentation pain and mixed pain, with 75% and 61% pain reduction (visual analog scale), respectively. Nociceptive pain patients had best pain relief initially (78% pain reduction) but it tended to decrease over the follow-up period to 57% pain reduction at final follow-up. The average pain reduction for all groups after 6 months was 67.5% and at last follow-up, it was 57.5%. Ten patients were satisfied with the delivery system and eleven reported improvement in their quality of life. In two patients, morphine was not able to adequately control the pain without producing undesirable side effects requiring the addition of clonidine to their infusion medication. In this series, 12 patients were considered successes and 4 patients were considered failures. In two patients, the intrathecal opioid therapy was unable to produce satisfactory pain relief and in the other two patients the pumps had to be explanted because of intolerable side effects. CONCLUSIONS In our experience, the administration of intrathecal opioid medications for nonmalignant pain is justified in carefully selected patients.

Nociceptin receptors in the rat spinal cord during morphine tolerance

The anatomical localization of nociceptin receptors was examined by in vitro quantitative autoradiography techniques in rat spinal cord sections by using [ 125 I –Tyr 14]nociceptin. [ 125 I –Tyr 14]nociceptin appeared to interact with a single class of binding sites ( K D=0.1 nM) present in the grey matter in all laminae of the spinal cord from cervical to sacral levels. Pre-incubation of sections in the presence of 150 mM NaCl, did not modify the radioligand affinity but significantly augmented the number of accessible binding sites and increased specific binding of [ 125 I –Tyr 14]nociceptin differentially on each laminae. In particular, the superficial layers of the dorsal horn exhibited the highest density of sites after pre-wash. Continuous intrathecal infusion of morphine produced a tolerance accompanied by a significant increase in nociceptin site density in the superficial layers. Thus, nociceptin binding sites may have different properties dependent upon the layer and may be up-regulated during the process of opioid-induced tolerance.

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

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. 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. 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. 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.

Long-Term Intrathecal (IT) Administration of Opioid and Bupivacaine Relieved Intractable Pain in a Patient with Familial Amyloidosis Polyneuropathy: A Case Report

Introduction. At the present time, there is no reliable method or drug for effective relief of the severe pain caused by the amyloldotic polyneuropathy (AP). Objective. To explore the possibility of relieving this type of pain by intrathecal (IT) infusion of opioid (morphine or buprenorphine), with or without bupivacaine. Patients, Materials and Methods. A 49-year-old male AP patient with Intractable pain in the low back, lower abdomen, and lower extremities. Opioids (up to 20 mg parenteral morphine-eq/day), and epidural injections of morphine (up to 36 mg/day) failed to provide long-term satisfactory pain relief. Therefore, an IT catheter was inserted via the L3-L4 interspace with its tip located at the L1-L2 intervertebral disk. Results. Intermittent IT injections of morphine from 5 to 30 mg per day, for 124 days, and continuous IT infusion of morphine (2-4 mg/ml), combined with bupivacaine (1.0-2.0 mg/ml), in daily rates from 2 to 12 ml (median = 9.5) for another 67 days, were associated with occurrence of seizures, suspected to be caused by the IT morphine. Therefore, the IT morphine was replaced with IT buprenorphine. Thereafter, the pain was treated with IT infusion of buprenorphine (0.06 mg/ml) and bupivacaine (1.25 mg/ml) in daily rates from 4 to 13 ml (median = 5) for another 676 days, until the patient's death, for reasons unrelated to the IT treatment. He experienced satisfactory pain relief with daily doses of IT opioid from 4.5 to 39 mg morphine-eq (median = 19.6 mg) and IT bupivacaine from 0 to 20 (median = 12.5). The mean visual Analog Scores (VASmean), decreased from 7 to 0 (out of 10), the gait improved; and nocturnal sleep increased from 1 to 7-8 hours. Respiratory insufficiency (attributed to an an IT daily dose of ∼ 5 mg morphine) and orthostatic hypotension, pareses, and urinary retention occurring at low doses of (12-18 mg/day) of IT bupivacaine were recorded. The patient had the IT treatment for 867 days, of which 777 days (> 90%) were spent at home. Conclusion. Long-term IT administration of opioid and bupivacaine provided satisfactory long-term pain relief in a patient with refractory pain due to AP.

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.