Continuous Intrathecal Morphine Administration Research Articles

Polysaccharopeptide from Trametes versicolor blocks inflammatory osteoarthritis pain-morphine tolerance effects via activating cannabinoid type 2 receptor

Analgesia with opioids such as morphine is an effective clinical strategy for the treatment of cancer pain and chronic inflammatory pain. However, long-term use of morphine can cause morphine tolerance (MT), which limits the clinical application of opioids. Polysaccharopeptide from Trametes versicolor (TPSP) is a biologically active macromolecule that exerts anti-tumor, immune-enhancing and pain-relieving effects. In order to address the clinical problem of MT, herein, we investigated the inhibitory effect and mechanism of TPSP in rats with inflammatory pain-morphine tolerance. A chronic inflammatory osteoarthritis pain-morphine tolerance model was simulated by injection of complete Freund's adjuvant (CFA) through the ankle joint cavity and continuous intrathecal administration of morphine. Different doses of TPSP (50 μg/kg, 100 μg/kg and 200 μg/kg) were intrathecally administered for consecutive 3 weeks. Our results indicate that TPSP can significantly inhibit the development of morphine dependence and acute withdrawal in rats, alleviate the decrease of paw withdrawal mechanical threshold and heat stimulation retraction latency. In addition, mechanistically at the molecular level, these effects are elicited via up-regulation of the cannabinoid type 2 receptor, up-regulating the level of β-endorphin, and reducing the levels of IL-1, NO and PGE2. In summary, we report for the first time the application of TPSP as an adjunctive therapy strategy for the relief of MT in clinic.

Ultralow Dose of Naloxone as an Adjuvant to Intrathecal Morphine Infusion Improves Perceived Quality of Sleep but Fails to Alter Persistent Pain: A Randomized, Double-blind, Controlled Study.

This randomized, cross-over, double-blind, controlled study of continuous intrathecal morphine administration in patients with severe, long-term pain addresses whether the supplementation of low doses of naloxone in this setting is associated with beneficial clinical effects. All of the study subjects (n=11) provided informed consent and were recruited from a subset of patients who were already undergoing long-term treatment with continuous intrathecal morphine because of difficult-to-treat pain. The patients were (in a randomized order) also given intrathecal naloxone (40 ng/24 h or 400 ng/24 h). As control, the patients' ordinary dose of morphine without any additions was used. The pain (Numeric Rating Scale, NRS) during activity, perceived quality of sleep, level of activity, and quality of life as well as the levels of several proinflammatory and anti-inflammatory cytokines in the blood were assessed. The prestudy pain (NRS during activity) in the study group ranged from 3 to 10. A total of 64% of the subjects reported improved quality of sleep during treatment with naloxone at a dose of 40 ng per 24 hours as compared with 9% with sham treatment (P=0.024). Although not statistically significant, pain was reduced by 2 NRS steps or more during supplemental treatment with naloxone in 36% of subjects when using the 40 ng per 24 hours dose and in 18% of the subjects when using naloxone 400 ng per 24 hours dose. The corresponding percentage among patients receiving unaltered treatment was 27%. To conclude, the addition of an ultralow dose of intrathecal naloxone (40 ng/24 h) to intrathecal morphine infusion in patients with severe, persistent pain improved perceived quality of sleep. We were not able to show any statistically significant effects of naloxone on pain relief, level of activity, or quality of life.

Continuous Intrathecal Morphine Administration for Cancer Pain Management Using an Intrathecal Catheter Connected to a Subcutaneous Injection Port: A Retrospective Analysis of 22 Terminal Cancer Patients in Korean Population

BackgroundIntrathecal opioid administration has been used widely in patients suffering from severe cancer pain that is not managed with conventional modalities. However, the potential serious neurological complications from the procedure and the side effects of intrathecal opioids have made many clinicians reluctant to employ continuous intrathecal analgesia as a first-line therapeutic option despite its dramatic effect on intractable pain. We retrospectively investigated the efficacy, side effects, and complications of intrathecal morphine administration through intrathecal catheters connected to a subcutaneous injection port (ICSP) in 22 Korean terminal cancer patients with successful intrathecal morphine trials.MethodsPatient demographic data, the duration of intrathecal opioid administration, preoperative numerical pain rating scales (NRS) and doses of systemic opioids, side effects and complications related to intrathecal opioids and the procedure, and the numerical pain rating scales and doses of intrathecal and systemic opioids on the 1st, 3rd, 7th and 30th postoperative days were determined from medical records.ResultsIntrathecal morphine administration for 46.0 ± 61.3 days significantly reduced NRS from baseline on all the postoperative days. A significant increase in intrathecal opioids with a nonsignificant decrease in systemic opioids was observed on the 7th and 30th postoperative days compared to the 1st postoperative day. The most common side effects of intrathecal opioids were nausea/vomiting (31.8%) and urinary retention (38.9%), which were managed with conservative therapies.ConclusionsIntrathecal morphine administration using ICSP provided immediate and beneficial effects on pain scores with tolerable side effects in terminal cancer patients.

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.

Safety of chronic intrathecal morphine infusion in a sheep model.

The safety of chronically administered intrathecal morphine has been questioned. Therefore, the authors examined the behavioral and neurologic effects and neurotoxicity of continuous intrathecal morphine administration in sheep. Groups of three sheep were implanted with intrathecal infusion systems for the continuous administration of morphine (3, 6, 9, 12, or 18 mg/day) or saline at a fixed infusion rate of 1.92 ml/day beginning approximately 7 days after implantation. Sheep were examined daily for any changes in behavior or neurologic function. After 28-30 days, the animals were humanely killed. Cerebrospinal fluid samples were collected and analyzed for protein, erythrocytes and leukocytes, and morphine content. The spinal cord and meninges with the catheter in situ was removed en bloc and fixed in formalin for histologic analysis. Unilateral hind-leg gait deficits were observed in two of three animals in each of the 12- and 18-mg/day dose groups. Gross and microscopic evaluation of spinal cord tissue from these animals revealed intradural-extramedullary inflammatory masses that compressed the spinal cord at the catheter-tip and mid-catheter areas. This inflammation was ipsilateral to extremities that exhibited gait deficits and had acute and chronic cellular components. The toxicity of intrathecal morphine seems to be dependent on the amount of morphine infused, although the effects of dose versus concentration cannot be clearly distinguished in this study. Intrathecal morphine doses of 12- 18 mg/day produced inflammatory masses extending from the catheter tip down the length of the catheter within the subarachnoid space. Doses of 6-9 mg/day produced mild-to-moderate inflammation 5 cm cranial to the catheter tip. A dose of 3 mg/day produced no neurotoxicity and spinal histopathologic changes that were equivalent to those observed in the saline-treated animals.

Driving and intrathecal morphine administration

Since Belgian law recently set a limit to morphine concentration detectable in blood and urine while driving a vehicle, questions arose about the implications for the medical use of opiates. We determined morphine concentrations in whole blood and urine by gas chromatography–mass spectrometry in 15 patients on continuous intrathecal morphine administration. Effects on blood and urine concentration after water intake and the correlation with the intrathecal morphine daily dose were also evaluated. Our results confirm that, in all patients examined, the legally determined maximum blood morphine concentration of 20ng/ml was never exceeded. Even patients on high intrathecal morphine dose schedules did never reach the maximum legal blood concentration. However, morphine concentration in urine reached levels which exceeded by far the legally determined maximum concentration of 300ng/ml. Although legal actions against driving under the influence of morphine can only be taken after a positive urine and a subsequent positive blood sample, drivers on intrathecal opiates must be aware of the possibility of a positive roadside drug test.

Neurohistopathological findings after continuous intrathecal administration of morphine or a morphine/bupivacaine mixture in cancer pain patients.

As the number of terminal cancer patients receiving continuous intrathecal infusion of opioids and local anesthetics for relief of pain increases, we decided to investigate the post-mortem findings of the spinal cord, meninges and nerve roots of patients after continuous intrathecal administration of morphine and combined with bupivacaine. Neurohistopathological findings were obtained from 10 cancer patients [2 men and 8 women, 29-69 (median 52) yrs old] and 4 controls [4 men, 46-75 (median 64) yrs old]. The cancer patients had been treated for a mean of 98 (range 8-452) d with morphine/NaCl 0.9% or morphine/bupivacaine, administered through a polyamide lumbar catheter. Concomitant radiation therapy and chemotherapeutic drugs had been given to 5 and 6 patients, respectively. Cumulative doses of morphine ranged from 22 to 3895 mg, those of bupivacaine from 0 to 3250 mg and of sodium metabisulfite (antioxidant) from 0.6 to 97.4 mg. No macroscopic abnormalities of the catheter tract, dura, leptomeninges, nerve roots or spinal cord were found. Microscopically, focal foreign body giant cells were seen in 2 cases in the area of the catheter pathway both without any sign of inflammation. In one case treated for 103 d, an intrathecal reaction was found. This consisted of small aggregates of lymphocytes predominantly in the leptomeninges and focally in the cord parenchyma. No abnormalities were found in the other cases when using hematoxylin-eosin and Kluver or Bodian stained specimens, indicating neither myelin nor axonal damage. Microglial reactions were similar in both cancer patients and controls. The discrete and limited neurohistopathological findings in both catheter patients and controls suggest that intrathecal infusion of morphine and bupivacaine via a polyamide catheter is devoid of significant neurotoxic effects in cancer patients.

Long-Term Continuous Intrathecal Administration of Morphine and Bupivacaine at the Upper Cervical Level

Crul, Ben J. MD, PhD; van Dongen, Robert T. MD; Snijdelaar, Dirk G. MD; Rutten, Ewald H. MD Author Information

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.

Continuous intrathecal administration of morphine via an osmotic minipump in the rat

Morphine HCl dissolved in artificial CSF or artificial CSF were administered intrathecally on the dorsum of the lumbar enlargement in rats via ALZET® osmotic minipumps delivering 0.5 μl/h for 14 days. Significant analgesia as assessed by the hot plate test was observed for 3 days after the start of drug administration for both morphine and CSF. No analgesia was found in rats where the catheter was located away from the dorsum of the lumbar enlargement.