The safety and efficacy of KAI-1678- an inhibitor of epsilon protein kinase C (εPKC)-versus lidocaine and placebo for the treatment of postherpetic neuralgia: a crossover study design.

OBJECTIVE: Postherpetic neuralgia (PHN) occurs in approximately 10-20% of patients with herpes zoster, and the risk increases with age. In this clinical trial, we evaluated the analgesic properties of KAI-1678-an inhibitor of epsilon protein kinase C-in the treatment of neuropathic pain in patients with PHN. DESIGN: The study was a three-treatment period, double-blind, randomized, placebo and active comparator crossover trial evaluating subcutaneous infusions of KAI-1678 (25 mg), placebo, and lidocaine hydrochloride (700 mg; active comparator). PATIENTS: A total of 17 men and 6 women (N = 23) were enrolled after fulfilling diagnosis of PHN with pain persisting for ≥3 months after a segmental herpes zoster eruption. Patients had to have a mean average pain score of ≥4 points on an 11-point numerical rating scale (NRS; ranging from 0 to 10) based on at least three daily entries prior to participation in the subsequent treatment period. RESULTS: Overall, administration of KAI-1678 was generally safe and well tolerated. However, compared with placebo, KAI-1678 did not improve clinical pain scores as recorded using the NRS (0-10). In contrast, subcutaneous infusions of lidocaine were associated with a significant reduction in pain intensity at the end of the infusion. CONCLUSIONS: We conclude that KAI-1678 is not efficacious as an acute analgesic for chronic neuropathic pain because of PHN. However, for the first time, the results demonstrate that subcutaneous infusions of lidocaine are effective in treating neuropathic pain. The results of lidocaine treatment also indicate that the crossover study design was adequate to detect a clinically meaningful response in this analgesia study.

Beware the Tarlov cyst.

Tarlov cysts are sacral perineural cysts. This case report describes the clinical course after biopsy of a very large Tarlov cyst via laparoscopy, which was thought preoperatively to be an adnexal mass. It serves as a warning against attempting biopsy or resection of these lesions.

Anaesthesia underpins acute patient care in hospitals.

The Australian and New Zealand College of Anaesthetists (ANZCA) carried out a review of the roles of anaesthetists in providing acute care services in both public and private hospitals in Europe, North America and South-East Asia. As a result, ANZCA revised its education and training program and its processes relating to overseas-trained specialists. The new training program, introduced in 2004, formed the basis for submissions to the Australian Medical Council, and the Australian Competition and Consumer Commission/Australian Health Workforce Officials' Committee review of medical colleges. A revised continuing professional development program will be in place in 2007. Anaesthetists in Australia and New Zealand play a pivotal role in providing services in both public and private hospitals, as well as supporting intensive care medicine, pain medicine and hyperbaric medicine. Anaesthesia allows surgery, obstetrics, procedural medicine and interventional medical imaging to function optimally, by ensuring that the patient journey is safe and has high quality care. Specialist anaesthetists in Australia now exceed Australian Medical Workforce Advisory Committee recommendations.

Intrathecal catheter granuloma associated with isolated baclofen infusion.

Intrathecal (IT) baclofen is an effective management strategy for controlling spasticity in patients unresponsive to maximal oral therapy. We present the case of a 57-yr-old woman who was rendered quadriplegic after a complete spinal cord transection at the C6 level. Her course was complicated by severe spasms, which were uncontrolled despite titrating orally administered baclofen to 80 mg/d. IT baclofen testing was performed with good response, and administration was commenced via an implanted intrathecal pump 6 mo after the injury at an initial dose of 200 microg/d. Catheter revision was required 2 wk later as a result of catheter displacement. The initial IT baclofen dose was gradually increased to achieve good control at a level of 400 microg/d. After a period of stability lasting 38 mo, her lower limb spasms dramatically increased in severity and remained poorly controlled despite repeated dose increases. Contrast pumpogram and computed tomography myelogram were performed to exclude a mechanical cause for this apparent increase in baclofen requirement. These investigations revealed neither catheter displacement nor fracture as suspected but, rather, displayed the presence of a catheter tip-associated mass. Catheter tip granuloma has not previously been described in a patient receiving IT baclofen alone. This suggests that although uncommon, the possibility of catheter-associated granuloma must be considered in all patients receiving IT baclofen presenting with altered neurological function or significant increase in drug requirement.

Ketamine in chronic pain management: an evidence-based review.

Ketamine has diverse effects that may be of relevance to chronic pain including: N-methyl-D-aspartic acid, alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, kainate, gamma-aminobutyric acid(A) receptors; inhibition of voltage gated Na(+) and K(+) channels and serotonin, dopamine re-uptake. Ketamine has been in clinical practice for over 30 yr; however, there has been little formal research on the effectiveness of ketamine for chronic pain management. In this review we evaluate the available clinical data as a basis for defining the potential use of ketamine for chronic pain. Literature referenced in this review was obtained from a computer search of EMBASE and MEDLINE from 1966 through August, 2002. Search terms included ketamine, ketalar, pain, painful, analgesic, and analgesia. Abstracts were screened for relevance and publications relating to chronic pain use were obtained. Levels of evidence were stratified according to accepted guidelines (level I-IV). For central pain, there is level II and level IV evidence of efficacy for parenteral and oral ketamine. For complex regional pain syndromes, there is only level IV evidence of efficacy of epidural ketamine. For fibromyalgia, there is level II evidence of pain relief, reduced tenderness at trigger points, and increased endurance. For ischemic pain, a level II study reported a potent dose-dependent analgesic effect, but with a narrow therapeutic window. For nonspecific neuropathic pain, level II and level IV studies reported divergent results with questionable long-term effects on pain. For phantom limb pain and postherpetic neuralgia, level II and level II studies provided objective evidence of reduced hyperpathia and pain relief was usually substantial either after parenteral or oral ketamine. Acute on chronic episodes of severe neuropathic pain represented the most frequent use of ketamine as a "third line analgesic," often by IV or subcutaneous infusion (level IV). In conclusion, the evidence for efficacy of ketamine for treatment of chronic pain is moderate to weak. However, in situations where standard analgesic options have failed ketamine is a reasonable "third line" option. Further controlled studies are needed.

Conversion disorder after implant of a spinal cord stimulator in a patient with a complex regional pain syndrome.

IMPLICATIONS: This case history describes the treatment of a patient suffering with persistent pain. He was treated surgically with implantation of a spinal cord stimulator. After surgery, a partial paralysis that could not be explained medically and that was probably related to emotional factors occurred, and cognitive behavioral treatment was begun. This paper discusses the importance of considering social and psychological factors when medical treatment options are considered.

Multimodal analgesia and intravenous nutrition preserves total body protein following major upper gastrointestinal surgery.

BACKGROUND AND OBJECTIVES: This study examined whether perioperative multimodal analgesia (MMA) improves the effectiveness of intravenous nutrition (IVN) as a means of preventing protein wasting following major upper abdominal surgery (UAS). The MMA regimen utilized combined epidural opioid/local anesthetic and the systemic nonsteroidal anti-inflammatory drug (NSAID) ketorolac for 48 hours. METHODS: In a prospective, randomized, nonblinded study, 47 patients scheduled for major UAS were allocated to receive the following: MMA +/- intravenous lipid-based nutrition (IVN) or patient-controlled analgesia with opioids (PCA) +/- IVN. Pain scores, nitrogen balance, total body protein (TBP), arterial blood gases, and various hormones were measured. RESULTS: Pain control was significantly better in the MMA patients at rest and coughing. Only the MMA + IVN group maintained TBP, mean (+/-95% confidence interval) preoperative day 1, 10.5 (+/-1.0) kg; day 14, 10.7 (+/-1.2) kg, whereas TBP decreased in the other groups (P =.04). Nitrogen balance was significantly greater in patients receiving IVN on day 7 (P =.01), but there was no effect related to the analgetic regimen. Decreased PaO(2) seen on postoperative day 2 was not prevented by MMA. The hormonal response to surgery was not influenced by treatment modality, apart from a return to postprandial insulin levels on postoperative day 7 in those patients receiving IVN (P =.002). CONCLUSIONS: In conclusion, we have shown that the combination of MMA and IVN prevents protein loss and improves pain control after major UAS. Our results suggest that after UAS, MMA significantly reduced pain and, in combination with IVN, preserves total body protein and fat. This is the first direct evidence of such effects associated with a commonly used multimodal regimen.

Management of intrathecal catheter-tip inflammatory masses: a consensus statement.

OBJECTIVES: In a companion article, we synthesized current clinical and preclinical data to formulate hypotheses about the etiology of drug administration catheter-tip inflammatory masses. In this article, we communicate our recommendations for the detection, treatment, mitigation, and prevention of such masses. METHODS: We reviewed published and unpublished case reports and our own experiences to find methods to diagnose and treat catheter-tip inflammatory masses in a manner that minimized adverse neurological sequelae. We also formulated hypotheses about theoretical ways to mitigate, and possibly, prevent the formation of such masses. RESULTS: Human cases have occurred only in patients with chronic pain who received intrathecal opioid drugs, alone or mixed with other drugs, or in patients who received agents that were not labeled for long-term intrathecal use. Most patients had noncancer pain owing to their large representation among the population with implanted pumps. Such patients also had a longer life expectancy and exposure to intrathecal drugs, and they received higher daily doses than patients with cancer pain. Clues to diagnosis included the loss of analgesic drug effects accompanied by new, gradually progressive neurological symptoms and signs. When a mass was diagnosed before it filled the spinal canal or before it caused severe neurological symptoms, open surgery to remove the mass often was not required. Anecdotal reports and the authors' experiences suggest that cessation of drug administration through the affected catheter was followed by shrinkage or disappearance of the mass over a period of 2-5 months. CONCLUSIONS: Attentive follow-up and maintenance of an index of suspicion should permit timely diagnosis, minimally invasive treatment, and avoidance of neurological injury from catheter-tip inflammatory masses. Whenever it is feasible, positioning the catheter in the lumbar thecal sac and/or keeping the daily intrathecal opioid dose as low as possible for as long possible may mitigate the seriousness, and perhaps, reduce the incidence of such inflammatory masses.

Comparison of intermittent bolus with continuous infusion of epidural morphine in the treatment of severe cancer pain.

Twenty-eight patients with severe pain due to cancer, who could no longer obtain acceptable pain relief from optimised doses of oral opioids, were entered into a study which compared pain relief, satisfaction with pain therapy and estimates of neuropsychological functioning during treatment with spinally administered (i.e., epidural and intrathecal) morphine as either repeated bolus doses or as a continuous infusion. These measures of efficacy and side effects were repeated every 2 weeks until either the patient died (82% of patients), withdrew from the study or were no longer able to complete the tests due to deterioration of their condition. The mean (range) duration of treatment was 169 (6-537) days for those patients receiving continuous infusion and 140 (28-378) days for those patients receiving repeated bolus doses. There was no significant difference in visual analogue pain scores, pain relief scores and satisfaction scores between the bolus and infusion groups. Furthermore, low pain scores and high pain relief scores indicated that both treatment modalities provided effective pain control. Similarly, there was no significant difference between the two groups in the various tests used to assess depression or neuropsychological function (i.e., memory, vigilance, attention and processing). There was a significantly greater degree of dose escalation in patients receiving continuous infusion compared to patients receiving repeated bolus doses. For 6 patients in the infusion group the catheter was sited in the intrathecal space, as the dose requirements by the epidural route exceeded the delivery capacity of the pump. For 4 patients in the bolus group the catheter was similarly sited, due to pain on injection and leakage/blockage.(ABSTRACT TRUNCATED AT 250 WORDS)

Long-term spinal administration of morphine in cancer and non-cancer pain: a retrospective study.

Records of 313 patients who had been treated with spinal morphine via an implanted Port-A-Cath were reviewed. In 284 cases the Port-A-Cath was implanted for epidural delivery of morphine in patients with cancer-related pain. These patients were treated for a mean of 96 (range 1-1215) days. There was a wide variation in dose requirements, minimum daily dose ranging from 0.5 to 200 mg and maximum daily dose from 1 to 3072 mg. However, there was no clear trend to increasing dose as period of epidural morphine administration increased. The most frequent complications were pain on injection (12.0% incidence), occlusion of the portal system (10.9%), infection (8.1%) and leakage of administered morphine such that it did not all reach the epidural space (2.1%). In all but 1 case infections were limited to the area around the portal or along the catheter track. All infections resolved without sequelae following removal of the portal and/or administration of antibiotics. In 17 patients Port-A-Caths were implanted for the intrathecal delivery of morphine to control cancer-related pain. These patients also exhibited wide variations in morphine dose requirements. Port-A-Caths were also implanted for delivery of spinal morphine in 12 patients with chronic pain which was not related to cancer and which failed to respond to other therapies. These patients were treated for a mean of 155 (range 2-575) days. Port-A-Caths were removed from 7 of these patients, primarily due to infection (2 cases) and inadequate pain relief and pain on injection (2 cases).

The efficacy of transdermal fentanyl in the treatment of postoperative pain: a double-blind comparison of fentanyl and placebo systems.

Forty consenting patients scheduled for abdominal surgery were entered into a double-blind comparison of the efficacy of transdermal fentanyl (TTS-fentanyl) and placebo (TTS-placebo) in the treatment of postoperative pain. All patients were allowed supplementary pethidine (25-50 mg) if pain relief was inadequate provided that their respiratory rate was greater than 10 breaths/min and there was no pronounced CNS depression. Visual analogue pain scores (VAPS), sedation rating scores (SRS), blood samples for the determination of fentanyl concentration, blood pressure, pulse and respiratory rate were determined hourly for 48 h from the time of TTS system application. The first lot of TTS systems were removed after 24 h and a second lot were applied which remained in situ for a further 24 h. There was no significant difference between the patients in the TTS-fentanyl and TTS-placebo groups in the VAPS throughout the 0-12, 12-24, 24-36 and 36-48 h periods suggesting that the quality of pain relief was similar between the 2 groups. However, significantly less supplementary pethidine was administered to the TTS-fentanyl group in the 12-24, 24-36 and 36-48 h periods. In contrast, the amount of supplementary pethidine administered in the 0-12 h period was similar in both groups which was consistent with the long delay time (mean +/- S.D. value of 16.6 +/- 10 h) before clinically effective concentrations of fentanyl were obtained from the systems. The profile of side effects was similar in the 2 groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Failure of epidural opioid to control cancer pain in a patient previously treated with massive doses of intravenous opioid.

A patient with disseminated cancer pain failed to obtain pain relief despite the intravenous infusion of hydromorphone at a rate equivalent to over 7 g of morphine/day. Temporary pain relief occurred with an epidural injection of the local anesthetic lidocaine. Subsequently, the patient failed to obtain pain relief with a dose of epidural hydromorphone equivalent to approximately 3 g of morphine epidurally/day. At this time a syndrome of agitation, sweating, tachycardia and severe muscle cramps developed in the lower half of the body. After eliminating the possibility of spinal cord compression by diagnostic CT scanning, the patient was treated by reducing the dose of hydromorphone and adding local anesthetic, which provided pain relief but did not eliminate the severe muscle spasms and other symptoms. The addition of oral clonidine followed by clonidine dermal patch rapidly and completely eliminated the other symptoms, suggesting that the response was due to too rapid withdrawal of opioid. Maintenance of pain relief required the simultaneous administration of epidural bupivacaine and hydromorphone. A low-dose infusion of epidural bupivacaine was continued for more than 3 weeks and during this entire period the patient showed no evidence of motor or sympathetic block.

Combined neurogenic and nociceptive pain in a patient with Pancoast tumor managed by epidural hydromorphone and oral carbamazepine.

A 43-year-old male with a Pancoast syndrome suffered severe unrelieved pain for approximately 10 months after diagnosis. The results of administration and cessation of lidocaine and carbamazepine strongly suggest that a neurogenic component contributed to the severity of this patient's pain. This was also supported by a long period of previous sensory and motor loss in the upper limb and upper chest wall. Initially pain relief was attainable with a combination of oral carbamazepine and oral hydromorphone. However, as the patient's condition worsened, this combination produced only partial pain relief. Complete relief of the patient's pain was then attained only with a combination of epidural hydromorphone and oral carbamazepine. Hydromorphone was administered via an implanted, externalized silastic epidural catheter and infused by a miniaturized battery-operated pump which permitted a background infusion and the administration of patient and family-delivered boli. With this combination of oral carbamazepine and epidural hydromorphone, the patient was able to obtain complete pain relief for a period of 3 months until the time of death.

Estimation of methadone clearance: application in the management of cancer pain.

The long half-life and wide inter-patient variability in clearance of methadone make this drug difficult to use optimally. If a patient's methadone clearance is known, however, dose regimens can be devised to maintain any desired blood concentration and hence, since the effect of methadone is related to its concentration in the blood, pain relief. We investigated methods for determining methadone clearance. In 25 patients, clearance was estimated by monitoring blood methadone concentrations following an intravenous infusion. Estimates of clearance adequate for clinical purposes could be obtained by assaying only 10-12 blood samples collected over 30 h following the infusion. The blood sampling schedules were such that it was not necessary to collect samples during the night, so the procedure could be done on an outpatient basis. An advantage of this procedure is that it also allows estimation of the blood methadone concentration required to relieve pain. We also conducted a retrospective study of data from 185 patients whose methadone clearance we had determined, to identify factors which may give rise to the large inter-patient variation in clearance. Clearance tended to be high in patients taking phenytoin, spironolactone, verapamil or oestrogens, and low in patients taking amitriptyline. Patients with malignant disease as opposed to chronic benign pain, and patients 65 years of age or older, tended to have low clearance. Clearance was positively associated with haematocrit. An equation was constructed allowing methadone clearance to be predicted from knowledge of these factors. The predicted clearance, however, showed only a moderately strong correlation with measured clearance (r = 0.75), indicating that factors not investigated also had a major influence on methadone clearance.

The influence of drug polarity on the absorption of opioid drugs into CSF and subsequent cephalad migration following lumbar epidural administration: application to morphine and pethidine.

This study examines the influence of drug polarity on the rate and extent of drug absorption into cerebrospinal fluid (CSF) following lumbar epidural administration. Twelve patients with pain secondary to cancer were simultaneously administered both morphine (10 mg) and pethidine (50 mg) in 10 ml of normal saline via an epidural catheter inserted in the lumbar region (usually L2,3) and attached to a subcutaneously implanted portal reservoir. Frequent blood samples were collected to characterise the vascular uptake of both opioids. In addition, a single CSF sample was collected in each patient from the C7-T1 interspace at one of the following times: 10, 30, 60, 120, 180 and 240 min. There was a rapid vascular uptake of morphine from the epidural space with a mean (+/- S.D.) peak concentration of 173 +/- 80 ng/ml (range 52-345 ng/ml) and a time-to-peak concentration of 8 +/- 6 min (range 2-17 min). In contrast, the vascular uptake of pethidine was more variable with a mean (+/- S.D.) concentration of 274 +/- 294 ng/ml (range 80-1113 ng/ml) and the time-to-peak concentration was 21 +/- 26 min (range 2-75 min). There was a rapid absorption of pethidine across the dura mater into the CSF with peak CSF concentrations between 1400 and 1650 ng/ml occurring between 10 and 60 min in samples collected cephalad (C7-T1 interspace) from the administration point in the lumbar region. However, the peak morphine concentration in CSF was delayed relative to the pethidine peak and occurred at 120 min.(ABSTRACT TRUNCATED AT 250 WORDS)

A comparative study of the efficacy and pharmacokinetics of oral methadone and morphine in the treatment of severe pain in patients with cancer.

Eighteen patients suffering from cancer were entered into a study of the pharmacokinetics and efficacy of methadone and morphine in pain control. All patients had both clinical and radiological evidence of metastatic spread of their cancer and there were no significant differences in age, weight and sites of the primary cancer between the methadone (n = 9) and morphine (n = 9) groups. Blood opioid concentration, visual analogue pain scores (VAPS) and end-tidal percent carbon dioxide were measured before and after both an intravenous and oral dose of either methadone or morphine. Terminal half-lives (mean +/- S.D.) were 30.4 +/- 16.3 h and 2.7 +/- 1.2 h respectively for methadone and morphine while the clearance values (mean +/- S.D.) were 0.19 +/- 0.13 l/min and 1.16 +/- 0.47 l/min. The long half-life of methadone was associated with prolonged pain relief. However, the large variation in the half-life of methadone necessitated careful adjustment of the dosing interval in individual patients. There were pronounced differences in oral bioavailability between the two opioids: methadone, 79 +/- 11.7%, compared to morphine, 26 +/- 13% (mean +/- S.D.). Of greater clinical significance was the variability in these bioavailability estimates with a coefficient of variation of 15% for methadone compared to 50% for morphine. The combined effects of low and variable oral bioavailability for morphine may result in sub-therapeutic doses being administered as practitioners may be inhibited by the size of the effective oral morphine dose and may be confused by the variability in this dose compared to intramuscular doses. The initial oral dose of morphine varied from 15 mg 4 hourly to 150 mg 3 hourly, while the initial dose for methadone varied from 15 mg on alternate nights to 20 mg twice daily. There was no rapid escalation of daily opioid dose for either methadone or morphine when adequate pain control was provided rapidly at the start of treatment by the technique described in this study.