The Pharmacology of Spinal Opioids and Ziconotide for the Treatment of Non-Cancer Pain.

BACKGROUND: Intrathecal drug delivery has undergone a revitalization following a better understanding of this delivery route and its pharmacokinetics. Driven by patient safety and outcomes, clinicians are motivated to rethink the traditional spinal infusion pump patient selection criteria and indications. We review the current understanding of the pharmacology of commonly employed intrathecal agents and the clinical relevance. METHODS: Search strategies for data acquisition included Medline database, PubMed, Google scholar, along with international and national professional meeting content, with key words including pharmacology of opioids, intrathecal therapy, ziconotide, pharmacokinetics, and intrathecal drug delivery. The search results were limited to the English language. RESULTS: Over 300 papers were identified. The literature was condensed and digested to evaluate the most commonly used medications in practice, sto serve as a foundation for review. We review on-label medications: ziconotide and morphine, and off label medications including fentanyl, sufentail, and hydromorphine. CONCLUSION: Intrathecal therapy has level-one evidence for use for malignant pain and nonmalignant pain, with continued cost savings and improved safety. To most effectively serve our patients, a clear appreciation for the pharmacology of these commonly employed medication is paramount.

An implantable drug delivery system (IDDS) for refractory cancer pain provides sustained pain control, less drug-related toxicity, and possibly better survival compared with comprehensive medical management (CMM).

BACKGROUND: The randomized clinical trial of implantable drug delivery systems (IDDS) plus comprehensive medical management (CMM) versus CMM alone showed better clinical success at 4 weeks for IDDS patients. This 'as treated' analysis assessed if improvements in pain control, drug toxicity and survival were maintained over time. PATIENTS AND METHODS: We compared those who received IDDS with those who did not receive IDDS (non-IDDS). All patients had Visual Analogue Scores (VAS) for pain > or =5/10 on at least 200 mg morphine or equivalent daily. RESULTS: At 4 weeks, 46 of 52 (88.5%) IDDS patients achieved clinical success compared with 65 of 91 (71.4%; P=0.02) non-IDDS patients, and more often achieved > or =20% reduction in both pain VAS and toxicity [35 of 52 (67.3%) versus 33 of 91 patients (36.3%); P=0.0003]. By 12 weeks, 47 of 57 (82.5%) IDDS patients had clinical success compared with 35 of 45 (77.8%; P=0.55) non-IDDS patients, and more often had a > or =20% reduction in both pain VAS and toxicity [33 of 57 (57.9%) versus 15 of 45 patients (33.3%); P=0.01]. At 12 weeks the IDDS VAS pain scores decreased from 7.81 to 3.89 (47% reduction) compared with 7.21 to 4.53 for non-IDDS patients (42% reduction; P=0.23). The 12 week drug toxicity scores for IDDS patients decreased from 6.68 to 2.30 (66% reduction), and for non-IDDS patients from 6.73 to 4.13 (37% reduction; P=0.01). All individual drug toxicities improved with IDDS at both 4 and 12 weeks. At 6 months, only 32% of the group randomized to CMM and who did not cross over to IDDS were alive, compared with 52%-59% for patients in those groups who received IDDS. CONCLUSIONS: IDDS improved clinical success, reduced pain scores, relieved most toxicity of pain control drugs, and was associated with increased survival for the duration of this 6 month trial.

Current and future trends in spinal cord stimulation for chronic pain.

Spinal cord stimulation (SCS) is a reversible treatment for chronic pain that is gaining favor as a first-line therapy for many disease states. Because there are no addictive issues and no side effects systemically, the treatment is moving up the treatment continuum ladder. First used clinically in 1967, the procedure was used exclusively for failed back surgery syndrome. Over the past 30 years selection criteria, psychologic screening, and technology have improved. These advances have broadened the treatment options for many patients in pain. This review focuses on the selection, indications, techniques, new advances, complications, and outcomes involved with SCS. A review is provided for the treatment of radiculitis, failed back surgery syndrome, complex regional pain syndrome, peripheral neuropathies, pelvic pain, occipital neuralgia, angina, ischemic extremity pain, and spasticity. Technologic advances such as multi-lead and multi-electrode arrays are also discussed in regard to the impact these developments have on the clinical application of the therapy.

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.

Evidence-based review of the literature on intrathecal delivery of pain medication.

Evidence-based medicine depends on the existence of controlled clinical trials that establish the safety and efficacy of specific therapeutic techniques. Many interventions in clinical practice have achieved widespread acceptance despite little evidence to support them in the scientific literature; the critical appraisal of these interventions based on accumulating experience is a goal of medicine. To clarify the current state of knowledge concerning the use of various drugs for intraspinal infusion in pain management, an expert panel conducted a thorough review of the published literature. The exhaustive review included 5 different groups of compounds, with morphine and bupivacaine yielding the most citations in the literature. The need for additional large published controlled studies was highlighted by this review, especially for promising agents that have been shown to be safe and efficacious in recent clinical studies.

Clinical guidelines for intraspinal infusion: report of an expert panel. PolyAnalgesic Consensus Conference 2000.

Consensus guidelines developed by an expert panel are helpful to clinicians when there is variation in practice and lack of a firm evidence base for an intervention, such as intraspinal therapy for pain. An internet-based survey of practitioners revealed remarkable variation in practice patterns surrounding intraspinal therapy. This prompted an interdisciplinary panel with extensive clinical experience in intraspinal infusion therapy to evaluate the results of the survey, the systematic reviews of the literature pertaining to this approach, and their own clinical experience with long-term spinal infusions. The panel proposed a scheme for the selection of drugs and doses for intraspinal therapy, and suggested guidelines for administration that would increase the likelihood of a successful outcome. These expert panel guidelines were designed to provide an initial structure for clinical decision making that is based on the best available evidence and the perspectives of experienced clinicians.

Future directions in the management of pain by intraspinal drug delivery.

Management of pain by intraspinal delivery of drugs enables physicians to target specific sites of action. While this novel approach is gaining increasing use, well-designed studies are needed. A major limitation is the lack of published information on existing drugs used for intrathecal delivery. (The strengths and weaknesses of this information are reviewed in the accompanying literature review article.) Promising agents such as bupivacaine, hydromorphone, and morphine/clonidine combinations warrant further research in large prospective (ideally randomized and double-blind) clinical safety and efficacy studies. These studies may provide data for pain management guidelines, such as those included in the preceding paper. Research must also address issues of formulation, chemical stability/compatibility, pharmacokinetics, and toxicology during clinical development and drug approval. Finally, more basic studies and early phase trials of other potential agents for intrathecal pain management (e.g., gabapentin) are needed.

Intrathecal therapy for cancer and nonmalignant pain: patient selection and patient management.

Intrathecal drug delivery improves pain relief, reduces suffering, and enhances quality of life in the small proportion of patients who do not respond well to oral analgesics, including oral morphine. Although morphine is the "gold standard," and the only drug approved for intrathecal pain therapy in the United States, off-label use of alternative agents appears promising, particularly in patients with neuropathic pain. Careful patient selection and management are significant determinants of successful treatment outcomes. Patient selection criteria for cancer and nonmalignant pain are similar; however, a more comprehensive psychological and social assessment is required for patients with nonmalignant pain. In addition, all patients (those with cancer or nonmalignant pain) must exhibit a positive response to an epidural or intrathecal screening test. A multidisciplinary team approach, involving psychologists, nurses, physical therapists, social workers, and spiritual leaders should be used to manage patients. Current practices for patient selection and management, screening tests, and dosing guidelines for intrathecal drug delivery systems are discussed.

Panic symptomatology and anxiety sensitivity in older adults.

Panic symptomatology and anxiety sensitivity (AS) were evaluated in cognizant older adults (mean age over 80 years). Forty-nine percent of the participants reported some panic symptoms and 27% a panic attack during the past year. Symptomatic participants reported related distress, lifestyle restrictions, mild avoidance behavior and concern about future attacks. About half the symptomatic participants reported uncued panic attacks and approximately half the participants who experienced panic during the past year reported panic symptom onset after age 60. AS predicted significant unique variance in panic symptomatology even after controlling for life-stress and depression. AS may play an important role in the development of panic in older adults. Panic symptomatology significantly affects the life of many older adults and further evaluation is warranted.

Coronary artery muscle bridging causing class III angina in a patient with no coronary atherosclerosis.

The significance of coronary artery muscle bridging (MB) has been debated since its first angiographic description by Portsmann and colleagues in 1960 (1). The course is usually benign; however, angina, myocardial infarction, sudden death, arrhythmias, and complete heart block have been reported. In this article, we present a case of coronary artery muscle bridging which caused a patient with no angiographic evidence of atherosclerosis to experience Class III angina.

Cardiac conduction manifestations of Reiter's syndrome.

This study shows that conduction abnormalities may occur frequently in Reiter's syndrome of new onset or short duration. Since these conduction defects may be initially life threatening or may progress to life-threatening abnormalities, anyone with RS should be followed up. Because of the strong association between RS and HIV infection, we suggest HIV testing for all patients with RS. Anyone with RS should have an electrocardiogram, either to study symptoms or as a baseline if no symptoms exist.