TO THE EDITOR: We write in response to the letter by Awerbuch1 and agree with many of his points. He has raised an interesting issue regarding the assertion that chronic pain is itself a disease,2 suggesting it would then logically follow that the patient becomes the final arbiter of whether he or she has the “disease” and hence which treatment may or may not be appropriate. A disquieting development in this regard is the recent Declaration of Montréal, produced at the International Pain Summit of the International Association for the Study of Pain in September 2010.3 This declaration states that access to pain management should be considered a fundamental human right. The position of diagnosis is uncertain, and the only specific treatment modality mentioned is opioid therapy. While we are sure that the Declaration is noble in intent, where does it place a clinician who has concerns about prescribing opioids to a patient who demands them? It adds the legal threat of a breach of human rights if the patient is disaffected with a doctor’s decision on opioid prescribing. As Awerbuch and others4,5 have stated, the public health consequences of prescribed opioids are not trivial. Assessing the appropriate circumstances for their use requires an understanding of clinical evidence and due care, not dogma, moral coercion or forays into jurisprudence.

Portal vein thrombosis is a rare but well-reported complication after laparoscopic surgery. We present a case of portomesenteric venous thrombosis that occurred 8 days after a laparoscopicassisted right hemicolectomy. Systemic anticoagulation failed to improve symptoms. The early postoperative state precluded the use of transarterial thrombolytic therapy. Transjugular intrahepatic catheter-directed infusion of urokinase into the superior mesenteric vein resulted in clearance of thrombus and resolution of symptoms. The published data on laparoscopy-induced splanchnic venous thrombosis and transjugular intrahepatic intramesenteric thrombolysis are discussed.

The present study evaluated the safety and efficacy of patient-activated delivery of intrathecal morphine sulfate boluses delivered by way of a novel internalized intrathecal delivery system. Patients with refractory cancer pain or uncontrollable side effects were enrolled at 17 US and international sites in this prospective, open-label study. Pain relief, reduction in systemic opioid use, and reduction in opioid-related complications were analyzed both individually and together as a measure of overall success. One hundred forty-nine patients were enrolled and 119 were implanted. Average numeric analog scale pain decreased from 6.1 to 4.2 at 1 month and was maintained through month 7 (P < .01) and through month 13 (P < .05). Systemic opioid use was significantly decreased throughout the study (P < .01). Significant reduction in the opioid complication severity index was demonstrated at all 4 follow-up visits (P < .01). Overall success (≥50% reduction in numeric analog scale pain, use of systemic opioids, or opioid complication severity index) was reported in 83%, 90%, 85%, and 91% of patients at months 1, 2, 3, and 4, respectively. This study demonstrated that patients with refractory cancer pain or intolerable side effects achieved better analgesia when managed with patient-activated intrathecal delivery of morphine sulfate via an implanted delivery system.

Twenty-four patients with severe pain related to cancer completed a randomised, double-blind, double-dummy, crossover study examining morphine pharmacokinetics and pharmacodynamics when the same 24-h morphine dose was administered using two modified release oral morphine formulations; either one dose of Kapanol (a new sustained release polymer coated pellet formulation administered in capsule form, Glaxo Wellcome group of companies) per 24 h, or MS Contin (Purdue Frederick Company, Connecticut, USA) administered at 12-h intervals. The morphine dose was optimised for each patient using an immediate release morphine solution in the lead-in period to provide the most favourable balance between pain relief and side-effects. Patients were then randomly allocated to receive their 24-h morphine dose as either Kapanol or MS Contin in period 1. Patients recorded daily measures of pain relief and morphine related side-effects (morphine pharmacodynamics) in a diary. Patients were admitted to the Pain Management Unit on the morning of day 7 (+/- 1 day) and frequent blood samples were collected for 24 h following the 10:00 h dose to fully characterise the pharmacokinetic profile for morphine and its metabolites at steady state. Morphine pharmacodynamics and the amount and timing of rescue medication (dextromoramide) were also recorded during this time. Period 2, which commenced at 10:00 h on day 8, was identical to period 1 except the modified release formulations were changed. The pharmacokinetic profile of Kapanol exhibited a significantly higher Cmin (minimum plasma morphine concentration), less fluctuation in plasma morphine concentration throughout the dosing interval, a longer Tmax (time associated with the maximum morphine concentration) and a greater time that the plasma morphine concentration was > or = 75% of Cmax (an index of the control the formulation exerts over the morphine release rate) compared to that of MS Contin. Some of these pharmacokinetic differences (e.g., Cmin and fluctuation in plasma morphine concentration) were surprising given that the dosing interval for Kapanol (24 h) was double that of MS Contin (12 h). There was no significant difference between the Kapanol and MS Contin treatment phases in any of the pharmacodynamic parameters, morphine related side-effects, the percentage of patients taking rescue medication as well as the amount or time to the first dose of rescue analgesia on day 7 in periods 1 and 2, patient or investigator assessments of global efficacy at the end of periods 1 and 2, or patient treatment preference at the end of the study. Once a day Kapanol provided the same degree of pain relief and morphine related side-effects as 12-h MS Contin.

Twenty-six patients with severe pain associated with cancer were entered into a study where they were required to take morphine mixture for 7 days. Prior to this, their morphine dose had been optimised to provide the most favourable balance between pain relief and side effects. After 6 days of taking their optimised morphine dose at 4-hourly intervals, the patients were admitted to the Pain Management Unit such that the doses from 18:00 h on day 6 were taken under direct nursing supervision. Frequent blood samples were collected after the 10:00 h (dose 1), 14:00 h (dose 2) and 18:00 h (dose 3) on day 7. There was a significant difference between the 3 doses with respect to Cmax values for morphine with dose 3 > dose 1 > dose 2. Further, there was considerable variability in the percentage change of either dose 1 or dose 3 Cmax. values relative to dose 2. The Cnmax values of the active metabolite morphine-6-glucuronide (M6G), measured in 6 of the patients, for the 3 dosing intervals followed a similar trend to the parent drug; but only doses 1 and 2 differed significantly. Similar but less pronounced changes were observed in the area-under-curve parameter calculated for both morphine and M6G during the 3 dosing intervals. There were no significant differences in the Cmin or Tmax parameters for either morphine or M6G between the 3 dosing intervals. These results suggest intra-individual variation in the absorption of morphine or changes in the volume of distribution during the day. The clinical significance of these data concerns the possible mismatch between the chronopharmacokinetic variability in plasma morphine concentrations demonstrated in this communication and literature reports of circadian variability in patients' reports of pain.

The role of the morphine metabolites, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) in the analgesia observed following morphine administration is controversial. There is greater acceptance of the analgesic role ascribed to M6G while M3G is alternatively considered to be inactive or result in functional antagonism. Kapanol™/Kadian™ (Glaxo/Faulding) is a new sustained release morphine formulation consisting of polymer coated pellets in a capsule. Twenty-four patients completed a randomized, double-blind, two period, crossover study comparing 24 hourly Kapanol to 12 hourly MS Contino. The morphine metabolite profile was determined in a randomly selected subset of those patients (n = 8). The Cmax, Cmin, AUC, time that the plasma morphine concentration was ≥ 0.75 Cmax (for that metabolite) and fluctuations in plasma morphine concentrations were not significantly different (P > 0.05, repeated measures ANOVA) between the two formulations for either metabolite. However, the Tmax for both M6G (P

Methadone — unpredictable duration of action [5].

This case report provides radiographic evidence (CT scan with Iopamidol) to support the development of epidural injectate encapsulation in response to long-term epidural morphine injections via an implanted polyurethane catheter. The patient complained of intense low interscapular pain when the catheter was used for administration of epidural morphine for control of angina. The patient had previously enjoyed 3 months of excellent pain relief following the initiation of epidural morphine via an implanted portal device. The CT scan, with contrast dye injected via the epidural catheter, clearly showed loculation of the injectate and associated indentation of the spinal cord. It is significant to note that the dye in the encapsulated sheath occupied a significant proportion of the spinal canal extending from T7 to T9.

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)

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).

Gourlay, Geoffrey K.; Plummer, John L.; Cherry, David A.; Cousins, Michael J. Author Information

Fentanyl (1 microgram/kg body weight) was administered intravenously and via a lumbar epidural catheter (in random order) on 2 separate occasions to 6 patients with chronic pain associated with non-terminal disease states. Frequent blood samples were collected from an indwelling intravenous catheter and CSF samples were collected via spinal needles inserted in the cervical (C7-T1 interspace) and lumbar (L3.4 interspace) regions at 0, 5, 10, 20, 30 and 45 min after fentanyl administration. The concentration of fentanyl in blood and CSF samples were quantified by a sensitive and selective gas-liquid chromatography assay. Visual analogue pain scores (VAPS) were recorded every 5 min for the first hour. Coded syringes (one containing the appropriate fentanyl dose while the other contained an equivalent volume of saline) allowed the investigator administering the fentanyl and assessing VAPS to remain blinded as to which route of administration actually contained the fentanyl. There was minimal vascular uptake of fentanyl following epidural administration. Similarly, the permeation of fentanyl into cervical and lumbar CSF following intravenous administration was minimal and erratic such that only 4 of the 60 CSF samples had detectable fentanyl concentrations. In contrast, there was a rapid penetration of fentanyl across the dura mater following lumbar epidural administration. There was significantly fentanyl in lumbar CSF samples by 10 min in 5 patients, and by 20 min in all 6 patients. The mean maximum lumbar CSF concentration was 19.1 ng/ml, while the time associated with these maximum concentrations was 22.5 min. The mean maximum cervical CSF fentanyl concentrations were 10% of the lumbar CSF concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)

There are two muscular mechanisms of fecal continence. The anal sphincter squeezes the anal canal, thus lengthening it and increasing its resistance. The puborectalis kinks the distal rectum, preventing the transmission of intra-abdominal pressures into the anal canal. Balloon sphincterography simultaneously records the shape of the anal canal and distal rectum and measures the strength of the puborectalis and anal sphincter muscles. This allows the physician to evaluate the function of these important muscles in patients with symptomatic defecation disorders such as constipation, incontinence, and rectal prolapse. A cylindrical balloon is connected by a hose to a fluid reservoir filled with liquid barium. The deflated balloon is placed into the anal canal and inflated by raising the fluid reservoir in increments. Fluoroscopy visualizes the balloon's shape and video records the results. Quantitative sphincterogram measurements in patients with defecation disorders include (the three measurements in each category refer respectively to incontinent patients [N = 87], prolapse patients without incontinence [N = 26], and constipated patients [N = 65]); anorectal angle (degrees + S.D.): 114 + 28, 103 + 18, 95 + 19; anal canal length (mm + S.D.): 33 + 11, 38 + 10, 39 + 10; squeeze pressure (cm H2O + S.D.): 68 + 23, 80 + 16, 91 + 22, and opening pressure (cm H2O + S.D.): 52 + 25, 67 + 22, 81 + 24. The method is useful in identifying specific defects, such as paradoxic puborectalis contractions, that can cause constipation, and injuries to the sphincters that can cause incontinence. In over 280 patients with a wide variety of defecation disorders, sphincterography has yielded information not available by standard manometric techniques. It augments the findings of defecography.

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.