Primary Hydromorphone-Related Intrathecal Catheter Tip Granulomas: Is There a Role for Dose and Concentration?

BACKGROUND: Intrathecal drug delivery therapy has been used effectively in treating patients with intractable chronic pain. The development of an intrathecal catheter tip granuloma (ICTG) related to delivery of intrathecal opiates is a relatively infrequent, but potentially devastating complication. While there are many morphine-related ICTG cases described, reports of hydromorphone-related ICTG are limited. In addition, studies suggest a strong correlation between the use of higher doses and concentrations of intrathecal opiates and ICTG formation. OBJECTIVE: The objective of this study is to determine the incidence and the association of intrathecal hydromorphone dose, concentration, duration of treatment and concomitant agents with ICTG formation. STUDY DESIGN: This is a retrospective analysis of 101 consecutive patients implanted with intrathecal infusion delivery devices. Data were collected from chart review, and records of pump refills from the division of Pain Medicine of University Hospitals or outsourced to a home pump refill service. RESULTS: From a cohort of 101 consecutively implanted patients, 69 were treated with intrathecal hydromorphone and followed up postimplant for an average of 33.5 ± 24 months (range 0-93 months; 95% CI of 27-39 months). The incidence of ICTG in our patient population was 8.7% during this period of time postimplant with mean time to granuloma detection 35.1 ± 7.9 months. Patients developing granuloma (n = 6) were treated with a combination of intrathecal hydromorphone and bupivacaine infusion. Exposure time to intrathecal agents was not different between the granuloma and nongranuloma group. Monthly dose increase of hydromorphone was higher in granuloma group vs. non-granuloma group (58 ± 34 mcg/month n = 6 vs. 25 ± 8 mcg/month n = 63). Four out of six granuloma cases occurred with low dose and concentration of IT hydromorphone (160-370 mcg/day; 0.75-1.0 mg/mL concentration). Intrathecal bupivacaine dose was not different between groups. A subset of patients was treated with intrathecal fentanyl and bupivacaine. No intrathecal granulomas occurred in this patient cohort. CONCLUSION: This is the first clinical report demonstrating an association of hydromorphone with intrathecal granulomas, particularly at low doses and concentrations of hydromorphone. This study supports the notion that using low dose of IT opioids might not protect against ICTG development but that the level of exposure and type of opioid used in IT space might be highly correlated with ICTG development. Further research and recommendations related to chronic intrathecal opioid infusions are necessary to raise awareness of significant incidence of ICTG and development of tests to isolate patient populations at high risk.

Ziconotide Combination Intrathecal Therapy for Noncancer Pain Is Limited Secondary to Delayed Adverse Effects: A Case Series With a 24-Month Follow-Up.

OBJECTIVES: The efficacy and safety of ziconotide as a single agent has been evaluated in few short-term clinical trials and open-label studies. Ziconotide use is challenging given its adverse effect (AE) profile. The objective of this study is to describe the long-term efficacy and AEs of ziconotide used as an adjunct to other intrathecal (IT) agents in chronic noncancer pain patients. MATERIALS AND METHODS: A case series of chronic noncancer pain patients who had suboptimal pain control from IT therapy. Ziconotide was introduced in the IT infusion mixture after a successful ziconotide trial. Pain scores, IT doses, as well as AEs were recorded and analyzed from trial to initial ziconotide infusion and up to 24 months. RESULTS: Fifteen patients underwent ziconotide trials. Four subjects failed the trial, and 11 proceeded to continuous ziconotide treatment. Seven out of 11 patients experienced AEs resulting in ziconotide discontinuation. Two of the seven subjects who required discontinuation of ziconotide had improved pain. Four subjects were able to continue IT ziconotide through 24 months. CONCLUSIONS: A high incidence of AEs limits the usefulness of IT ziconotide as adjunct therapy. Our results are limited by the size of our patient population; however, they represent a long follow-up period, which is limited in most current publications on this IT peptide. While ziconotide is a needed IT agent, more studies are necessary to better understand the factors that would improve the treatment to trial ratio as well as the long-term efficacy of IT ziconotide treatment.

Complex [corrected] regional pain syndrome: what specialized rehabilitation services do patients require?

Complex [corrected] regional pain syndrome (CRPS) is a complex disorder, the optimal treatment of which requires an interdisciplinary approach encompassing medical, interventional, psychological, and rehabilitation services that emphasize the role of physical and occupational therapies. The central focus of treatment is the restoration of function, utilizing a systematic, coordinated, and progressive set of therapeutic strategies. The poorly delineated pathophysiology and variable course of CRPS suggest that individualized strategies are required for optimal management, but also mean that carefully controlled trials of physiotherapy are difficult to conduct. This article presents a brief review of the nature and pathophysiology of CRPS, the medical and psychological approaches that have been found to be effective, and a review of the current trends in rehabilitation.

Combination of intrathecal opioids with bupivacaine attenuates opioid dose escalation in chronic noncancer pain patients.

OBJECTIVE: The purpose of this study was to examine the effect of intrathecal (IT) coadministration of bupivacaine with opioids during the initial phase of opioid titration and up to 1 year after implantation of an IT drug delivery system (IDDS). DESIGN: The study was designed as a retrospective study. OUTCOMES ANALYZED: The outcomes analyzed for this study were pain relief, oral opioid consumption, IT opioid, and bupivacaine dosage. METHODS AND PATIENT POPULATION: The patient population for this study were consecutively implanted patients over a period of 6 years in a tertiary single center with multiple practitioners. In this retrospective study, 126 consecutive noncancer intractable pain patients were implanted with IDDS and initiated with an IT opioid (O) as a single medication or an IT opioid and bupivacaine (O + B). Pain intensity, amount of oral opioids, dose, rate, and concentration of IT opioids and bupivacaine, and number and type of IT medication used were recorded at preimplant, implant, and at 3, 6, and 12 months postimplant. INTERVENTION: The intervention used for the study was the IT delivery device implant. RESULTS: Significant reduction in pain intensity was observed in both groups at 12 months postimplant (O group: baseline 7.42 ± 2.1 to 5.85 ± 2.8 [n = 72, P < 0.001]; O + B group 7.35 ± 2 to 5.03 ± 2.4 (n = 54; P < 0.001]). The combination of opioids with bupivacaine from the start of IT infusion treatment resulted in a reduced progression of opioid dose escalation in comparison to patients started with opioids (O group). The rate of increase of IT opioids in the O group at 12 months was 535 ± 180%, whereas in the O + B, the dose increase was significantly lower at 185 ± 85% (P < 0.004). In both groups, there was a statistically significant decrease in oral opioid consumption compared with preimplant doses. CONCLUSION: Concomitant initial coadministration of IT bupivacaine with opioids blunts the rate of IT opioid dose escalation during the first year after implant of an IDDS. More studies are necessary to thoroughly examine IT opioid dose escalation and the effects of addition of bupivacaine to IT opioids. Blunting IT opioid dose escalation may be a beneficial long-term effect of IT bupivacaine.

Age-dependent intrathecal opioid escalation in chronic noncancer pain patients.

BACKGROUND: Age and gender may exert important influences on opioid responsiveness and chronic pain. These effects have not been explored in the setting of chronic intrathecal (IT) opioid therapy. The objective of this study was to evaluate the effect of age and sex on IT opioid requirements during the first year after implantation of an intrathecal drug delivery system (IDDS) in chronic noncancer pain patients. DESIGN: Retrospective study. METHODS AND PATIENT POPULATION: In this retrospective study, 135 chronic noncancer pain patients consecutively implanted with IDDSs for opioid therapy had their first year postimplant records examined. RESULTS: Similar pain relief was achieved at 12 months after implant in both age groups. Relative to the dose at implant, younger patients had significantly higher rates of IT opioid dose escalation compared with older patients at 12 months (750 ± 450% in patients ≤50 years old vs 195 ± 120% in patients >50 years old, P < 0.001). Oral opioid consumption was significantly decreased at 12 months in the older patient population (140 ± 89 to 62 ± 35 mg/day at 12 months, P < 0.001, n = 85), while in the younger patient group, there was no change in oral opioid consumption (128 ± 81 mg/day to 105 ± 140 mg/day at 12 months, P = 0.65, n = 50). Gender-based analysis (55% males and 45% females) revealed similar reductions in pain scores during the first year postimplant. Oral opioid consumption was significantly higher in females (126 ± 138 mg) vs males (79 ± 89 mg) at 12 months postimplant; however, IT opioid dose escalation at 12 months postimplant was not statistically different between males and females. CONCLUSION: IT opioid dose escalation occurs more steeply in the younger (under 50 years old) IDDS patient population without a concomitant significant decrease in oral consumption of opioids. Age-dependent changes may have important clinical implications on the effectiveness of IT opioid therapy in noncancer pain and its potential complications.