Long-term outcomes during treatment of chronic pain with intrathecal clonidine or clonidine/opioid combinations

To evaluate the effectiveness of intrathecal clonidine or clonidine/opioid admixture for the treatment of chronic pain states, a retrospective chart audit of 15 patients seen by the Pain Medicine and Neurosurgical Services was performed. Subjects included 9 men and 6 women aged 26-86 years. Diagnoses included complex regional pain syndrome, neuropathic pain, and cancer pain. All patients received a trial of single-shot and/or short-term infusion of clonidine. Those reporting a significant reduction in pain, or at least 50% reduction in their visual analog scale (VAS), received long-term therapy. Intrathecal clonidine as a single-shot dose, infusion, or as intrathecal polytherapy did not improve VAS scales from pre-treatment values in 5 patients. Ten patients reported significant pain relief or >50% decrease in VAS scores with the initial trial and received long-term therapy. Two received clonidine alone for 7-11 months before the therapy failed; others failed after just a few days. Seven of eight initially responded to clonidine alone (75-950 microg/day) before failing and requiring a second drug. Three received hydromorphone (200-8000 microg/day) and four morphine (0.15-15 mg/day) with clonidine. Four patients then failed 2-drug therapy (duration 6-21 months). Two continue with intrathecal clonidine/hydromorphone (duration 19-29 months) and 1 with clonidine/morphine (duration 21 months). After initiation of intrathecal clonidine, one patient reported good relief with clonidine/morphine until his death 5 months later. In this population, intrathecal clonidine was of limited utility for most patients. It may be of benefit for subset(s) of patients, but in our experience, duration of relief is typically <18 months.     

Positive effect of regional analgesia (RA) in terminal stage paediatric chondrosarcoma: a case report and the review of the literature.

A 10-year-old girl was treated for progressive left pelvic chondrosarcoma and severe local pain radiating to the ipsilateral lower extremity. Despite high doses of opioids, pain was poorly controlled and treatment resulted in urine retention and constipation. Positive effect on pain (143 out of 181 days) was obtained by regional analgesia. Continuous lumbar epidural opioid infusion led to pain relief and disappearance of symptoms. Port-catheter dysfunction necessitated a change of epidural catheter and the patient was treated that with morphine, bupivacaine and clonidine plus clonazepam which resulted in relief of constipation and restoration of urinary function. The patient subsequently developed an abscess required or subarachoid infusion (morphine associated with clonazepam, clomipramine and corticosteroids). Later bilateral controlateral cordotomy was performed due to absence of analgesia and the patient subsequently died of tumour progression.     

Management of postoperative pain after T6 corpectomy: use of epidural bupivacaine and sufentanil--a case report

The objective of this case report is to discuss the successful postoperative analgesic management in a patient who had disseminated rectal cancer pain and failed to obtain pain relief despite high-dose intravenous hydromorphone. A 45-year-old male had metastatic rectal cancer involving multiple vertebrae. After a T6 corpectomy, the patient failed to obtain effective pain relief with massive doses of parenteral opioids. The epidural catheter was placed under fluoroscopy. The patient subsequently failed to obtain relief with epidural administration of bupivacaine and hydromophone. Epidural sufentanil was used to obtain adequate pain control. Postoperative epidural analgesia is a technique worthy of consideration for patients with extreme opioid dependency for corpectomy. Epidural sufentanil can successfully be administered for postoperative pain control for patients receiving a large dose of opioids for cancer pain.     

Opioid‐Free Perioperative Analgesia for Hemicolectomy in a Patient With Opioid‐Induced Delirium: A Case Report and Review of the Analgesic Efficacy of the Alpha‐2 Agonist Agents

Abstract: Surgical pain in patients with documented opioid‐induced delirium can be difficult to treat. We present a case of a patient undergoing laparoscopic hemicolectomy effectively treated with an opioid‐free, alpha‐2 adrenoreceptor agonist analgesic regimen. Case report: A 21‐year‐old woman with persistent abdominal pain presented to the operating room for laparoscopic hemicolectomy for redundant right colon. Her medical history included a recently diagnosed postoperative opioid‐induced delirium. Epidural infusion with local anesthetic offered partial pain relief with sensory levels of T9‐L2. With the addition of dexmedetomidine infusion in the immediate postoperative period, the patient was comfortable with pain scores of 1 to 2/10 on Numerical Rating Scale (NRS). On postoperative day 1, the infusion was discontinued and the clonidine, 12 μg/hours was added to the epidural bupivacaine. With increased sedation 48 hours later, neuraxial clonidine was discontinued in favor to transdermal clonidine 0.1 mg/week, which was maintained until hospital discharge. Pain scores were maintained at 2 to 3/10 on NRS for the next 3 days when increased abdominal distention because of abscess formation rendered a new surgical intervention. The analgesia for the exploratory laparoscopy was maintained using epidural clonidine and bupivacaine infusion as well as intravenous dexmedetomidine, which were maintained another 2 days. Pain scores remained minimal until discharged home 3 day later. Discussion: Nonopioid analgesic regimens are beneficial in patients at risk of postoperative cognitive dysfunction attributable to opioids. Successful postoperative analgesia was achieved in our patient by alternating various routes of administration of alpha‐2 adrenoreceptor agonists.     

Hydromorphone--review of pharmacological properties and therapeutic efficacy with special regard to a controlled release preparation

Hydromorphone is a micro receptor agonist opioid. According to WHO recommendations, hydromorphone is to be classified in step III of pain therapy. An oral formulation with a prolonged duration of action of 12 hours has been evaluated only recently. The controlled release capsule is especially suited for the regular twice a day administration in cases of severe and persistent pain. The oral formulation of hydromorphone increases the number of opioid analgesics available for pain therapy in step III. Hydromorphone is recommended when morphine fails to produce sufficient pain relief (despite increase of doses) or causes intolerable side effects (despite treatment of symptoms). In principle, no differences in efficacy of morphine and hydromorphone are to be expected. However, clinical experience shows that changing one opioid analgesic to another one can improve the treatment of patients so that hydromorphone may replace another opioid analgesic to which a patient fails to respond well or develops side effects. The dose of hydromorphone equivalent to 2 times 30 mg controlled release morphine is about 2 times 4 mg. The values for the absorption, bioavailability and maximum plasma concentration after the administration of controlled release hydromorphone every 12 hours -of three times the dose- are equivalent to those of an immediate release tablet given every 4 hours. In several open label and controlled studies, hydromorphone proved to be of good efficacy in the treatment of acute and persistent pain, especially in patients with severe cancer pain. With regard to the incidence of side effects, no significant differences between morphine and hydromorphone could be established. In general, the side effects of hydromorphone are typical for opioid analgesics. DISCUSSION: In conclusion, controlled release hydromorphone seems to be well suited for the control of severe chronic pain when given twice daily.     

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.     

Histological findings after long-term infusion of intrathecal ketamine for chronic pain: a case report.

Ketamine, a selective, noncompetitive N-methyl-D-aspartate (NMDA)-receptor antagonist, is able to alter pain perception at the spinal level. Little clinical data exist on the intrathecal and epidural use of ketamine in chronic pain. Histopathologic findings after intrathecal injection of ketamine with and without preservatives are rarely reported. This outcome was evaluated in a 72-year-old woman with abdominal pain due to cancer who was treated with the intrathecal application of bupivacaine, clonidine, and morphine. We reached satisfactory pain relief with the addition of ketamine to the mixture for 7 days. On postmortem, focal lymphocytic vasculitis close to the catheter injection site was found. This finding has not been described previously after long-term application of ketamine intrathecally. The intrathecal infusion of ketamine with preservative, or the mixture of ketamine, clonidine, morphine, and bupivacaine resulted in isolated lymphocytic vasculitis of the spinal cord and leptomeninges without any clinical signs of neurological deficit.     

Differences in the ratios of morphine to methadone in patients with neuropathic pain versus non-neuropathic pain.

The use of methadone in the treatment of cancer pain is becoming more attractive mainly because of its known efficacy, lack of active metabolites, and low cost. Methadone also blocks the n-methyl-D-aspartate (NMDA) receptor, and this property may result in other clinical advantages. Because of this capacity of methadone to block the NMDA receptors, we have hypothesized that the equianalgesic dose ratio of hydromorphone or morphine to methadone will be different in patients with neuropathic pain than in patients with non-neuropathic pain. To explore this hypothesis, we reviewed computerized patient records and determined the ratio of morphine and hydromorphone (expressed as morphine subcutaneous equivalent dose) to methadone in patients who underwent rotation from morphine or hydromorphone to methadone. We found that the ratio of morphine subcutaneous equivalent dose to methadone is between 5 and 7, which is different from previously described dose ratios. However, our study failed to show a difference in the ratios of patients with neuropathic or non-neuropathic pain syndromes.     

Decreased local toxicity with subcutaneous diamorphine (heroin): a preliminary report.

We report the cases of 5 patients who developed severe local toxicity during the subcutaneous administration of morphine sulphate and hydromorphone hydrochloride. All patients required site changes more frequently than once every 24 h due to redness, swelling, or pain while receiving morphine or hydromorphone. All patients showed prolongation in the duration of sites of infusion once an equianalgesic dose of diamorphine hydrochloride (heroin) was started. No change in pain control or systemic toxicity was detected with diamorphine. These findings suggest that diamorphine could be a useful alternative for patients who develop severe toxicity to subcutaneous morphine or hydromorphone.     

Stability, compatibility, and safety of intrathecal bupivacaine administered chronically via an implantable delivery system

OBJECTIVE: The only agent approved by the U.S. Food and Drug Administration for chronic intrathecal infusion for the treatment of chronic pain is morphine sulfate. In patients who do not experience adequate relief from intrathecal opioids, bupivacaine is frequently added to increase efficacy. The studies reported here were conducted to demonstrate the stability and compatibility of bupivacaine in a commonly used implantable infusion system and the long-term clinical safety of this therapy. METHODS: A commercially available bupivacaine solution (7.5 mg/ml) was incubated at 37 degrees C for 12 weeks with intact delivery systems and with the individual materials that comprise the fluid pathway. Intermittent samples were collected and analyzed using liquid chromatography. Materials chronically exposed to bupivacaine were analyzed for mechanical integrity. One hundred eight patients treated with intrathecal bupivacaine (average dose: 10 mg/d, range: 2-25 mg/d) and opioids for an average duration of 86 weeks were monitored clinically (patient interviews and neurologic examinations) approximately every 4 weeks. RESULTS: Bupivacaine concentrations remained greater than 96% of the starting material after chronic exposure to the delivery system materials or the intact pump-catheter systems. and the mechanical integrity of the delivery system and materials remained intact. When combined with intrathecal morphine or hydromorphone, no clinical evidence of drug-induced toxicity or complications was observed in any patient. Supplementing opioid therapy with bupivacaine allowed the pain patient to continue to be effectively managed using an implantable intrathecal delivery system. CONCLUSIONS: Bupivacaine is stable and compatible with a commonly used implantable drug infusion system. In this study, chronic supplementation of intrathecal opioids with bupivacaine was a safe method for providing continued management of chronic pain of cancer or noncancer origin.     

Double-blind, randomized, controlled trial of local anesthetic use for iliac crest donor site pain.

Autogenous iliac crest bone grafts are often used for persons undergoing anterior cervical fusion (ACF). Study findings have shown that pain at the iliac crest donor site can often be more severe than that at the primary operation site. A method used to eliminate pain after bone harvesting involves infiltration of a local anesthetic directly into the site. This study examined the efficacy of local anesthetic infiltration in the control of donor site pain, utilizing a randomized, double-blind, placebo-conrolled design. All participants received standard postoperative intravenous and oral analgesic. Those in the study group also received six injections of bupivacaine hydrochloride 0.25% into the donor site, while participants in the placebo group received normal saline injections. Participants receiving bupivacaine (n = 14) consistently reported lower hip pain scores than participants receiving the placebo (n = 8), with significant differences noted 3 hours after the first and second doses of the study drug. The bupivacaine group's mean morphine intake for the first 24 hours after surgery was found to be lower (32 mg; placebo 44 mg), whereas participants younger than 49 years who received bupivacaine were found, on average, to have stayed in the hospital one day less (3.6 days) than placebo group participants (4.5 days). Younger participants receiving bupivacaine required less morphine and had, on average, a reduced length of stay. The clinical implication of using local anesthetic for the relief of donor site pain suggests that it is a safe and efficacious technique.     

Neurological impairment during long-term intrathecal infusion of bupivacaine in cancer patients: a sign of spinal cord compression

Adequate pain relief in patients with far advanced cancer sometimes requires intrathecal (IT) administration of a combination of opioids and local anesthetics. Tumor progression as well as the IT administration of local anesthetics can lead to neurologic dysfunction during treatment. Five patients showed symptoms of compression of the cauda equina or spinal cord shortly after the start of combined IT administration of morphine and bupivacaine in a dosage usually not associated with neurologic symptoms. Unexpectedly, neurologic evaluation suggested compression of the cauda equina and spinal cord, which was confirmed radiographically. Manifestation of new neurologic symptoms during low dose bupivacaine infusion intrathecally might therefore be an early indicator of space-occupying processes within the spinal canal in cancer patients.     

The effect of pH-adjusted 2-chloroprocaine on the duration and quality of pain relief with a subsequent continuous epidural bupivacaine infusion.

A randomized, double-blind true experimental design with a post-test only was chosen to determine if the addition of sodium bicarbonate to 2-chloroprocaine would result in a longer duration of epidural analgesia, as well as increase the quality of pain relief in stage I parturients receiving a continuous bupivacaine epidural infusion. The experimental group (number (N) = 16) received sodium bicarbonate and 2-chloroprocaine followed by a continuous bupivacaine epidural infusion. The control group (N = 15) received normal saline and 2-chloroprocaine followed by a continuous bupivacaine epidural infusion. Only ASA I or II patients in stage I labor were included in this study. Measures of pain perception were made using a self-report, visual analog scale. Measures also were made of the quality and duration of block over time, the intensity of motor block over time, and the blood pressure over time. The cephalad dermatome level of analgesia was determined by pinprick. A record of the need for a supplemental bolus of local anesthetic to maintain a sensory level of T-10 was also recorded. The mean self-perceived level of pain was significantly different for the two groups (P = .024). Moreover, the pattern of self-perceived level of pain over time differs for the two groups in a significant way (P = .023). Additional bolus injections occurred nine times in the control group and six times in the experimental group. The differences were not found to be significant (P > .106). The differences in time and amount of local anesthetic delivered were also found to be trivial (P > .80).(ABSTRACT TRUNCATED AT 250 WORDS)     

Neuropathological findings after continuous intrathecal administration of S(+)-ketamine for the management of neuropathic cancer pain

Questions have been raised about the potential neurotoxicity of the neuraxial use of ketamine although ketamine and its active enantiomer S(+)-ketamine have been used intrathecally and epidurally (caudally) for the management of perioperative pain and in a variety of chronic pain syndromes. Clinical experience following neuraxial administration of S(+)-ketamine has been documented without reference to local central nervous system toxicity following this approach. In addition, there are no preclinical safety data regarding stability, compatibility, and neurotoxicity on intrathecal use of single S(+)-ketamine or combinations of S(+)-ketamine, morphine, bupivacaine, and clonidine. In the present case, the continuous intrathecal administration of S(+)-ketamine, in combination with morphine, bupivacaine, and clonidine resulted in adequate pain relief in a patient suffering from intractable neuropathic cancer pain. However, postmortem observation of the spinal cord and nerve roots revealed severe histological abnormalities including central chromatolysis, nerve cell shrinkage, neuronophagia, microglial upregulation, and gliosis. Based on our results, neuraxial administration of S (+)-ketamine cannot be recommended for clinical practise before a systematic study of toxicology of neuraxial S(+)-ketamine in animals or humans has been performed.     

Extended-duration agents for perioperative pain management

Perioperative pain management has drastically evolved over the years to satisfy current unmet needs. Intermittent delivery of drugs has been replaced by continuous delivery systems involving oral, neuraxial, and peripheral nerve block routes of administration. One current standard of perioperative pain management is an epidural injection of an opioid such as morphine, fentanyl, or hydromorphone, with or without the addition of a local anesthetic, such as bupivacaine. Although this method is extremely effective in controlling pain during the most critical 48-hour period postoperatively, it also has its disadvantages. Risks associated with indwelling epidural catheters include infection, adverse effects, and spinal hematoma. The development of extended- and controlled-release drug delivery systems has revolutionized perioperative pain management. This class of drugs comprises MS Contin (Purdue Pharma LP, Stamford, CT), OxyContin (Purdue Pharma LP), Opana ER (Endo Pharmaceuticals, Chadds Ford, PA), and DepoDur (Endo Pharmaceuticals). There are also phase II trials in progress examining controlled-release formulations of local anesthetics. This review discusses extended- and controlled-release agents administered perioperatively.     

Epidural mass associated with lack of efficacy of epidural morphine and undetectable CSF morphine concentrations

A case is presented in which epidurally administered morphine failed to provide the expected extent and duration of pain relief. The patient had severe back pain in the upper lumbar and low thoracic regions and epigastric pain which was presumed to be caused by widespread metastatic deposits in the vertebral column from a prostatic carcinoma. The lack of clinical effect of epidural morphine was shown to be related to the unexpected presence of an epidural mass which was located below the dermatomal region for the patient's pain. Myelography and a CT scan indicated that the mass effectively compressed the subarachnoid space, thereby preventing the rostral spread of morphine in the cerebrospinal fluid (CSF) following lumbar epidural administration, resulting in inadequate pain relief.     

Continuous epidural morphine treatment for intractable pain in terminal cancer patients

In patients with intractable cancer pain who failed to respond to conservative and neurosurgical procedures for pain relief, repeated injections of epidural morphine were found to be beneficial.A small dose of morphine (2–4 mg per injection) relieved pain for 6–24 h. A permanent subcutaneous epidural catheter led to successful ambulatory treatment without complications. The implantation of the epidural catheter is a minor surgical procedure, done under local anesthesia and is considered safe even in terminal cancer patients.     

Intrathecal coadministration of bupivacaine diminishes morphine dose progression during long-term intrathecal infusion in cancer patients.

OBJECTIVE: To determine the difference in intrathecal morphine dose progression between a continuous intrathecal infusion of a morphine/bupivacaine mixture and morphine for pain relief in patients with cancer. DESIGN: Patients were treated with intrathecal drugs in a randomized study and followed prospectively until death. SETTING: Institute for Anesthesiology, Department of Pain Treatment, University Hospital Nijmegen, St Radboud, The Netherlands. PATIENTS: Twenty patients with cancer were selected for intrathecal treatment because of either side effects or inadequate relief during conventional pain treatment. INTERVENTIONS: Intrathecal drug infusion rates and medication were adjusted according to pain relief and side effects. OUTCOME MEASURES: Progression of intrathecal morphine dose during a phase of adequate analgesia in both groups following regression analysis and analysis of possible treatment related side effects. RESULTS: The combination of intrathecal morphine and bupivacaine resulted in a diminished progression of the intrathecal morphine dose (slope of regression line = 0.0003 vs. 0.005, p = 0.0001) during a phase of stable analgesia in comparison with the morphine group. No serious side effects presented. CONCLUSION: The diminished intrathecal morphine dose increase in the combination group is considered to be due to a synergistic effect of bupivacaine on the intrathecal morphine-induced antinociception. A dose increment during long-term intrathecal infusion in cancer patients appears to be related to both disease progression and tolerance phenomena.     

Amputation and the prevention of phantom pain

Although it has been proposed that preoperative analgesia with epidural administration of analgesics may prevent long-term phantom pain, published results to date have been contradictory and controversial. In this case report, we describe a 41-year-old man with local recurrence of squamous cell carcinoma of the anus who underwent a hemipelvectomy. Preoperatively he had a significant neuropathic pain syndrome requiring oxycodone 60 mg every 4 hours. An epidural infusion of morphine and bupivacaine was started 24 hours preoperatively and discontinued on the third postoperative day. Over the next 10 days the oxycodone was gradually decreased and eventually discontinued prior to discharge. A review of the literature reveals conflicting reports on the benefit of preoperative epidural pain management in the prevention of postoperative pain syndromes. Conflicting research and conclusions of commentators leaves unanswered questions for clinicians. Nevertheless, we do know that we need to provide the best pain relief for patients both before and after amputation. This may require a combination of the oral, subcutaneous or intravenous, and epidural routes.     

Mode of delivery following labor epidural analgesia: influence of ropivacaine and bupivacaine.

Epidural analgesia is a popular and effective method for pain relief during labor. Bupivacaine is a commonly used local anesthetic for labor epidural analgesia. Ropivacaine is an amino acid local anesthetic that is structurally related to bupivacaine with a similar potency and duration, but ropivacaine has less cardiac toxicity than bupivacaine and produces less motor blockade. These properties make ropivacaine a desirable local anesthetic agent for obstetrical analgesia. The purpose of the present study was to compare the cesarean section and instrumental delivery rates for patients receiving labor epidural analgesia using bupivacaine and ropivacaine. The medical records of 500 consecutive patients receiving bupivacaine for labor epidural analgesia were reviewed. After a 3-month familiarization period for ropivacaine, the records of 500 consecutive patients receiving ropivacaine for labor epidural analgesia similarly were reviewed. The groups did not differ demographically. The instrumental delivery rate was 14.2% for the bupivacaine group and 9.8% for the ropivacaine group. The cesarean section rate was 14% for the bupivacaine group and 10.2% for the ropivacaine group. At our facility, the use of ropivacaine decreased both cesarean section and instrumental delivery rates when compared with bupivacaine in the population studied.