Intrathecal morphine

Johnston IN, Milligan ED, Wieseler-Frank J, Frank MG, Zapata V, Campisi J (2004) A role for proinflammatory cytokines and fractaUdne in analgesia, tolerance, and subsequent pain facilitation induced by chronic intrathecal morphine. J Neurosci 24(33) 7353-7365 Kim YS, Panganiban AT (1993) The full-length tat protein is required for TAR-independent, post-transcriptional trans activation of human immunodeficiency virus type 1 env gene expression. J Virol 67(7) 3739-3747... 

Gerber HR. Intrathecal morphine for chronic benign pain. Best Pract Res Clin Anaesthesiol. 2003 17 429—442. 

MECHANISM OF ALLODYNIA EVOKED BY INTRATHECAL MORPHINE-3-GLUCURONIDE IN MICE... 

Glavina, M. J., and Robertshaw, R. (1988). Myoclonic spasms following intrathecal morphine. 

Jonston, I. N.j Milligan, E. D., Wieseler-Frank, J., Frank, M. G., Zapata, V., Campisi,J., Langer, S., Martin, D., Green, P., Fleeshner, M., Leinwand, L., Maier, S. F., et al. (2004). A role for proinflammatory cytokines and fractalkine in analgesia, tolerance, and subsequent pain facilitation induced by chronic intrathecal morphine. J. Neurosci. 24, 7353-7365. 

Komatsu, T., Sakurada, C., Sasaki, M., Sanai, K., Tsuzuki, M., Bagetta, G., Sakurada, S., and Sakurada, T. (2007a). Extracellular signal-regulated kinase (ERK) and nitric oxide synthase mediate intrathecal morphine-induced nociceptive behavior. Neuropharmacology 52, 1237—1243. 

Penn, R., and Paice, J. (1987). Chronic intrathecal morphine for intractable pain. J. Neurosurg. 67, 182-186. 

Yaksh, T. L., and Harty, G. J. (1988). Parmacology of the allodynia in rats evoked by high dose intrathecal morphine.. Pharmacol. Exp. Ther. 244, 501—507. 

Kalso, E. (1983). Effects of intrathecal morphine, injected with bupivacaine, on pain after orthopaedic surgery. Br.J. Anaesth. 55, 415-422. 

Biphalin has a broad therapeutic window. Intrathecal morphine has a 50% MPE for tail flick analgesia at a dose of 2.5 pg per rat. A 10-fold higher dose produces rigidity and respiratory depression, causing death. In contrast, biphalin has a 75% MPE of 0.005 pg per rat. Increasing the biphalin dose... 

Hylden JLK, Wilcox GL (1980) Intrathecal morphine in mice a new technique. Eur J Pharmacol 67 313-316... 

In a randomized, double-blind study, 64 patients undergoing total knee arthroplasty received either intrathecal morphine 0.3 mg or intrathecal diamorphine, 0.3 mg in 0.3 ml, with 2-2.5 ml of 0.5% heavy spinal bupivacaine (3). The patients given morphine had significantly greater analgesia at 4, 8, and 12 hours postoperatively. The incidence of opioid-related adverse effects was not significantly different between the groups. 

Riad T, Williams B, Musson J, Wheatley B. Intrathecal morphine compared with diamorphine for postoperative analgesia following unilateral knee arthroplasty. Acute Pain 2002 4 5-8. 

In selected cases the full range of techniques of local and regional anaesthesia may be used, including extradural and intrathecal morphine (p. 360). 

Intolerable adverse effects or inadequate analgesia occur in 10-15% of patients with chronic pain given continuous intrathecal morphine. Hydromorphone is a semisynthetic derivative of morphine used extensively in the management of cancer pain. It is more soluble than morphine, has a slightly shorter duration of action, and is about five times more potent when given systemically. 

A patient who was receiving modified-release morphine for mahgnant pain had a respiratory arrest after intrathecal bupivacaine 12.5 mg. She recovered after treatment with naloxone. Another patient who was taking modified-release morphine was given intrathecal morphine 10 mg and bupivacaine 7.5 mg. He had respiratory distress and became comatose. Morphine-induced respiratory depression was not diagnosed and the patient subsequently died. In both cases, respiratory distress and sedation was probably due to opioid action in the absence of the stimulating effect of pain on respiration, due to the intrathecal bupivacaine (198). 

There have been another two studies of the analgesic effect of intrathecal morphine in children (34,35). In a prospective, double-blind study, 30 children (aged 9-19 years) scheduled for spinal fusion were randomly allocated to a single dose of saline or intrathecal morphine 2 or 5 pg/kg after surgery, a PCA device provided access to additional intravenous morphine (34). The doses of 2 and 5 pg/kg had similar analgesic effectiveness and adverse effects profiles (nausea, vomiting, pruritus). There were no episodes of severe respiratory depression. Low-dose intrathecal morphine supplemented with PCA morphine provides better analgesia than PCA morphine alone. 

In a smaller prospective, open, uncontrolled study, 12 children (3-6 years of age) were given either intermittent intrathecal morphine 5 pg/kg qds or a continuous infusion of a mixture of bupivacaine (40 pg/kg/hour) and morphine (0.6 pg/kg/hour) for intense postoperative pain after selective dorsal rhizotomy (35). The bupivacaine/ morphine mixture provided better analgesia with fewer adverse effects. The incidence of pruritus was 83% with morphine compared with 33% with bupivacaine/mor-phine. Otherwise the adverse effects were similar. 

Low-dose intrathecal morphine (0.3 mg) plus 0.5% spinal bupivacaine and patient-controlled intravenous morphine (given as a 1 mg bolus with a 5-minute lockout period) has been compared with patient-controlled intravenous morphine alone in 38 patients undergoing knee surgery in a randomized, double-blind study (40). The former combination provided effective analgesia with a low and non-significant incidence of emesis, pruritus, and respiratory depression. 

In a double-bhnd, randomized, uncontrolled study in 150 women to compare intrathecal morphine 100 micrograms plus ketoprofen, intrathecal morphine 200 micrograms, or epidural morphine 3 mg, postoperative nausea or vomiting occurred in 16,28, and 26% respectively (47). The incidence of itching was least in those given intrathecal morphine 100 micrograms. The results were unequivocal and did not justify preferring any one of the techniques as better or safer. 

Intrathecal morphine provides adequate postoperative analgesia in orthopedic surgery, but commonly causes urinary retention, pruritus, and nausea and vomiting. Finding the optimal dose of analgesic effect with minimal adverse effects is still the main objective of most papers published on morphine (49,50). 

In a randomized, double-blind study in 143 patients scheduled for total hip surgery the optimal dose of intrathecal morphine was as low as 0.1 mg (51). The patients were allocated to four groups depending on the dose of morphine used (0.025, 0.05, 0.1, and 0.2 mg). The incidence of pruritus, nausea and vomiting, and urinary retention, and the consumption of antiemetics did not differ among the groups. 

Subhypnotic doses of propofol (20 mg) given to 120 women receiving intrathecal morphine after cesarean section had no significant effect on pruritus (55). Higher success rates have been reported for propofol with non-obstetric patients, suggesting that labor-related factors may perpetuate this adverse effect. 

Yeh HM, Chen LK, Lin CJ, Chan WH, Chen YP, Lin CS, Sun WZ, Wang MJ, Tsai SK. Prophylactic intravenous ondansetron reduces the incidence of intrathecal morphine-induced pruritus in patients undergoing cesarean delivery. Anesth Analg 2000 91(l) 172-5. 

Gall O, Aubineau JV, Berniere J, Desjeux L, Murat I. Analgesic effect of low-dose intrathecal morphine after spinal fusion in children. Anesthesiology 2001 94(3) 447-52. 

Palmer CM, Emerson S, Volgoropolous D, Alves D. Dose-response relationship of intrathecal morphine for postcesarean analgesia. Anesthesiology 1999 90(2) 437 4. 

Slappendel R, Weber EW, Dirksen R, Gielen MJ, van Limbeek J. Optimization of the dose of intrathecal morphine in total hip surgery a dose-finding study. Anesth Analg 1999 88(4) 822-6. 

Beilin Y, Bernstein HH, Zucker-Pinchoff B, Zahn J, Zenzen WJ. Subhypnotic doses of propofol do not relieve pruritus induced by intrathecal morphine after cesarean section. Anesth Analg 1998 86(2) 310-13. 

In a double-blind, placebo-controUed study in 24 elderly patients scheduled for elective total hip replacement who were randomized to either intrathecal morphine 160 pg or nalbuphine 400 pg postoperatively, when the pain score was greater than 3 cm on a visual analogue scale, nalbuphine produced significantly faster onset and shorter duration of analgesia (5). Both opioids produced adequate maximal pain rehef in aU patients. The adverse effects profile was umemarkable in both groups. 

Intravenous nalbuphine 3 mg (n — 101) has been compared with intravenous propofol 20 mg (n = 90) in a double-blind, randomized study, to determine efficacy in the treatment of intrathecal morphine-induced pruritus after cesarean delivery 10 minutes after the drug was administered (6). Nalbuphine was significantly more effective, especially in cases of moderate but not severe pruritus. Adverse effects such as reduced analgesia and increased nausea, vomiting, sedation, and dizziness were not significantly different between the two groups. 

Fournier R, Van Gessel E, Macksay M, Gamulin Z. Onset and offset of intrathecal morphine versus nalbuphine for postoperative pain relief after total hip replacement. Acta Anaesthesiol Scand 2000 44(8) 940-5. 

Charuluxananan S, Kyokong O, Somboonviboon W, Lertmaharit S, Ngamprasertwong P, Nimcharoendee K. Nalbuphine versus propofol for treatment of intrathecal morphine-induced pruritus after cesarean delivery. Anesth Analg 2001 93(l) 162-5. 

Culebras X, Gaggero G, Zatloukal J, Kern C, Marti RA. Advantages of intrathecal nalbuphine, compared with intrathecal morphine, after cesarean delivery an evaluation of postoperative analgesia and adverse effects. Anesth Analg 2000 91(3) 601-5. 

The incidence of opioid-induced pruritus varies widely, and depends on the opioid used and its mode of administration. The highest incidence (up to 80%) is associated with intrathecal morphine. The pruritus is usually localized to the area of the face that is innervated by the trigeminal nerve. A central encephalinergic mechanism has been proposed to explain this localization. The pruritus is often difficult to treat and responds poorly to conventional treatments, except for naloxone and propofol 10-15% remain unresponsive. Naloxone reversibihty of opioid-induced pruritus supports the existence of an... 

In a prospective randomized, double-blind, placebo-controlled study in 100 patients scheduled for elective orthopedic surgery and presenting with pruritus induced by epidural or intrathecal morphine, intravenous ondansetron 8 mg was effective in 70% of cases and placebo in 30% (23). Ondansetron was well tolerated, did not change the degree of analgesia, and was not associated with adverse effects usually associated with ondansetron, such as headache, abdominal pain, and cardiac dysrhythmias. 

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