Effectiveness and Safety of Intrathecal Drug Delivery Systems for the Management of Cancer Pain: A Systematic Review and Meta-Analysis

ObjectivesIntrathecal drug delivery systems (IDDS) and spinal cord stimulation (SCS) have been proposed and assessed for the management of cancer pain; however, such treatments remain underused. We conducted a systematic review to evaluate the effectiveness and safety of IDDS and SCS for cancer pain.Materials and MethodsElectronic databases MEDLINE, CENTRAL, EMBASE, and WikiStim were searched from 1988 to March 2021. Randomized controlled trials and observational studies of adults with pain related to cancer or its treatment who received an implantable IDDS or SCS were eligible for inclusion. The primary outcome of the review was change in pain intensity from baseline to the last available follow-up, measured using a visual analog scale or numerical rating scale. The protocol for this review is registered on PROSPERO (CRD42021240717).ResultsA total of 22 studies (24 reports) included a total of 3043 participants who received either IDDS or SCS for cancer pain. Eight studies reporting data for 405 participants with an IDDS could be included in the meta-analysis of pain intensity that showed a statistically significant reduction at the latest posttreatment follow-up time compared with baseline (mean difference [MD], −3.31; 95% CI, −4.18 to −2.45; p < 0.001). Six studies reporting data for 325 participants with an IDDS could be included in the meta-analysis of pain intensity that showed a statistically significant reduction up to one month after treatment compared with baseline (MD, −3.53; 95% CI, −4.06 to −3.00; p < 0.001). A meta-analysis including studies of participants with either an IDDS or an SCS device showed similar results. Improvements in other outcomes following implantation of IDDS also were observed. Postdural puncture headache was the most reported complication, whereas urinary retention, nausea, and vomiting were commonly reported side effects.ConclusionOur findings suggest that IDDS is effective in reducing pain intensity for patients with cancer pain when compared with pretreatment.     

The Application of Failure Modes and Effects Analysis Methodology to Intrathecal Drug Delivery for Pain Management

ObjectiveThis study aimed to utilize failure modes and effects analysis (FMEA) to transform clinical insights into a risk mitigation plan for intrathecal (IT) drug delivery in pain management.MethodsThe FMEA methodology, which has been used for quality improvement, was adapted to assess risks (i.e., failure modes) associated with IT therapy. Ten experienced pain physicians scored 37 failure modes in the following categories: patient selection for therapy initiation (efficacy and safety concerns), patient safety during IT therapy, and product selection for IT therapy. Participants assigned severity, probability, and detection scores for each failure mode, from which a risk priority number (RPN) was calculated. Failure modes with the highest RPNs (i.e., most problematic) were discussed, and strategies were proposed to mitigate risks.ResultsStrategic discussions focused on 17 failure modes with the most severe outcomes, the highest probabilities of occurrence, and the most challenging detection. The topic of the highest-ranked failure mode (RPN = 144) was manufactured monotherapy versus compounded combination products. Addressing failure modes associated with appropriate patient and product selection was predicted to be clinically important for the success of IT therapy.ConclusionsThe methodology of FMEA offers a systematic approach to prioritizing risks in a complex environment such as IT therapy. Unmet needs and information gaps are highlighted through the process. Risk mitigation and strategic planning to prevent and manage critical failure modes can contribute to therapeutic success.     

Intrathecal Drug Delivery Systems for Cancer Pain Control: Insights on Current Contemporary Practices in the US

ObjectivesAmong patients with cancer with moderate to severe, intractable pain, intrathecal drug delivery using an intrathecal drug delivery system (IDDS) offers effective pain control. In this study, we evaluate the trends of IDDS therapy among patients with cancer, associated comorbidities, complications, and outcomes, using a large representative US administrative inpatient data base.Materials and MethodsThe Nationwide Inpatient Sample (NIS) data base contains data from 48 states and the District of Columbia. The NIS was used to identify patients with cancer who underwent IDDS implantation between 2016 and 2019. Patients with cancer with intrathecal pumps for the treatment of chronic pain were identified using administrative codes. Baseline demographics, hospital characteristics, type of cancer associated with IDDS implantation, palliative care encounters, hospitalization costs, length of stay, and prevalence of bone pain were evaluated in the study.ResultsA total of 22,895 (0.32%) individuals with hospital admission for IDDS surgery were included for analysis among 7.06 million individuals with cancer in the final cohort. The IDDS cohort consisted of patients predominantly in the 65-to-79 years age group (40.49%), female sex (50.42%), and Caucasian ethnicity (75.82%). The top five cancers in patients receiving IDDS were lung (27.15%), colorectal (24.9%), liver (16.44%), bone (8.01%), and liver (7.99%) cancer. In addition, the length of stay was six days (interquartile range [IQR] four–nine days) and the median cost of hospital admission was $29,062 (IQR $19,413–$42,261) in the patients who received an IDDS. These factors were greater than those in patients without IDDS.ConclusionsA very few patients with cancer received IDDS in the US during the study period. Despite recommendations supporting its use, there are significant racial and socioeconomic disparities in IDDS use.     

Initiation of Intrathecal Drug Delivery Dramatically Reduces Systemic Opioid Use in Patients With Advanced Cancer

ObjectivesPain is common in cancer, affecting more than 70% of patients with advanced disease. Intrathecal drug delivery systems (IDDS) are a well-established treatment for patients with refractory cancer pain, improving pain control and reducing associated side effects. To date, details of systemic opioid use before and after IDDS implant have not been reported.Materials and MethodsWe conducted a retrospective review of patients at Huntsman Cancer Institute-University of Utah treated with IDDS for cancer pain from May 2014 to May 2018. Oral, transdermal, and parenteral opioid use before IDDS implant was compared to use 30 days postoperatively.ResultsA total of 173 patients were included, 93% with stage IV disease. The pre-implant median daily oral morphine equivalent (OME) was 240 mg (interquartile range 130–390, range 0–2616 mg). OME doses >200 mg/day were required by 57% of patients, and >500 mg OME by 19% of patients. The post-implant median OME was 0 mg (interquartile range 0–0, range 0–480 mg) and 82.6% of patients discontinued systemic opioids completely. 11.0% of patients used <100 mg OME, and only 1.7% of patients used >200 mg OME. Mean OME decreased by 94% following IDDS implant (p < 0.0001) and all patients who continued to use systemic opioids required a lower OME compared to pre-implant.ConclusionsIn the largest cohort of patients with advanced cancer and refractory pain treated with IDDS, implantation was associated with a dramatic reduction in systemic opioid use 30 days postoperatively, with a large majority of patients discontinuing systemic opioids. Those patients that continued systemic opioids utilized significantly lower doses as compared to their pre-implant dose.     

The Effect of Measured Radiotherapy Dose on Intrathecal Drug Delivery System Function

ObjectivesRadiation therapy (RT) and intrathecal drug delivery systems (IDDS) are often used concurrently to optimize pain management in patients with cancer. Concern remains among clinicians regarding the potential for IDDS malfunction in the setting of RT. Here we assessed the frequency of IDDS malfunction in a large cohort of patients treated with RT.Materials and MethodsCancer patients with IDDS and subsequent RT at our institution from 2011 to 2019 were eligible for this study. Patients were excluded in the rare event that their IDDS was managed by an outside clinic and follow-up documentation was unavailable. Eighty-eight patients aged 22–88 years old (43% female, 57% male) representing 106 separate courses of RT were retrospectively identified. Patients received varying levels of radiation for treatment of cancer and cumulative dose to the IDDS was calculated. IDDS interrogation was subsequently performed by a pain specialist. Malfunction was recorded as deviation from the expected drug volume and/or device errors reported upon interrogation as defined by the manufacturer.ResultsTotal measured RT dose to the IDDS ranged from 0 to 18.0 Gy (median = 0.2 Gy) with median dose of 0.04 Gy/fraction (range, 0–3.2 Gy/fraction). Ten pumps received a total dose >2 Gy and three received ≥5 Gy. Eighty-two percentage of patients had follow-up with a pain specialist for IDDS interrogation and all patients underwent follow-up with a healthcare provider following RT. There were zero incidences of IDDS malfunction related to RT. No patient had clinical evidence of radiation related pump malfunction at subsequent encounters.ConclusionsWe found no evidence that RT in patients with IDDS led to device failure or dysfunction. While radiation oncologists and pain specialists should coordinate patient care, it does not appear that RT dose impacts the function of the IDDS to warrant significant clinical concern.     

Intrathecal Drug Delivery for the Treatment of Cancer-Associated Chronic Pain in Children

ObjectivesManagement of refractory cancer-associated pain can be particularly challenging. Regional anesthesia is an alternative modality to treat acute and chronic refractory pain. Intrathecal (IT) drug delivery of opioids and other adjuncts has been used to treat refractory cancer-associated pain. This method has been shown to be relatively safe and effective, often associated with fewer systemic side effects when compared to oral or IV opioid administration. While intrathecal drug delivery systems (IDDS) are regularly used in the adult cancer population for the treatment of refractory, chronic pain, there is limited evidence of similar use in the pediatric setting.Materials and MethodsWe performed a systematic review using conventional Preferred Reporting Items for Systematic Reviews and Meta-Analyses methodology to identify studies reporting IT drug delivery for the treatment of pediatric cancer-related pain. The primary outcome was satisfaction with analgesia categorized as “satisfactory” or “unsatisfactory.” Functional benefits, previous systemic pharmaceutical interventions, previous non-IT regional interventions, indication for IT drug delivery, IT drugs used, and method of delivery were collected.ResultsA total of 11 studies were identified, describing 16 patients with cancer-related pain treated with IT drug delivery. The average age of the cohort was 12.25 years, with ages ranging from 3 to 19 years. Most patients were adolescent (10/16). All patients had cancer diagnoses, with most patients suffering from solid tumor pain (14/16). Nearly all patients achieved satisfactory analgesia through IT drug delivery (15/16) and most reported functional benefits in addition to analgesia (13/16). Majority received IT drugs via external catheters (9/16). One severe complication of respiratory depression was reported, which resolved following naloxone administration.ConclusionsThere exist children with cancer whose pain is refractory to the standard approaches and may benefit from IT drug delivery. The existing data, although limited and of low tier evidence, suggest that IT drug delivery has been effective in the pediatric cancer population.     

Prevention of Intrathecal Drug Delivery Catheter‐Related Complications

In an effort to improve the performance of implantable intrathecal drug delivery systems, a group of physicians experienced in the management of such devices reviewed surgical practices and principles that were associated with low catheter‐related complication rates. Clinical study and postmarket data identified physicians whose patients experienced a relatively low rate of catheter‐related complications. Six of those physicians (three anesthesiologists and three neurosurgeons) reviewed the number and types of intrathecal drug pumps and catheters they had implanted, with an emphasis on the specific details of successful catheter implantation techniques. The authors pooled their experiences to reach a consensus on implant techniques that are associated with a low rate of postoperative complications. The authors found that complications were minimized by the use of specific methods for catheter placement that included: a mid‐to‐upper lumbar dural entry level, a shallow‐angle paramedian oblique insertion trajectory, and meticulous catheter anchoring and tunneling techniques. Systemic antibiotic prophylaxis, attention to pump pocket location, and surgical wound closure techniques also were important in reducing the incidence of postoperative device‐related complications. Their experience indicates that specific implantation techniques using a variety of catheters and accessories can be expected to reduce the incidence of complications after implantation of intrathecal drug administration systems.     

Severe Hypertension Following Accidental Clonidine Overdose During the Refilling of an Implanted Intrathecal Drug Delivery System

Background: Complications associated with intrathecal pumps may be linked to the surgical procedure, the implanted device, or the medication itself. Case Reports: Three patients treated chronically with intrathecal clonidine presented with clonidine overdose due to inadvertent extravasation during the refilling procedure. All patients experienced loss of consciousness and severe systemic hypertension that required aggressive parenteral treatment. Discussion: Clonidine is an alpha‐2 agonist with a nearly 100% bioavailability after oral or rectal administration. With high plasma concentration secondary to massive systemic overdose, the specificity for the alpha‐2 receptor is lost and an alpha‐1 agonist activity predominates and causes marked hypertension. Management of clonidine overdose consists of supportive therapy guided by signs and symptoms. Conclusion: Inadvertent injection into the subcutaneous pocket rather than the reservoir is rare but very dangerous as the drug cannot be retrieved and massive doses are involved. Signs and symptoms of systemic overdose with drugs commonly used in implanted drugs delivery system should be well known to ensure early diagnosis and treatment.     

Complications of Intrathecal Drug Delivery Systems

Objectives. To report complications associated with implant of the intrathecal drug delivery systems (IDDS). Patients and Methods. A retrospective review of the implant database was undertaken to determine various complications associated with the IDDS. A total of 122 patients were reviewed, 97 included in the final analysis, 25 excluded due to incomplete data. The complications of excluded patients were reviewed separately. The complications were divided in to categories pharmacologic, equipment, procedural, programming errors and psychological. The drugs used were morphine, dilaudid, fentanyl, sufentanil, baclofen, and marcaine. Results. There were 60 men and 37 women. A total of 43 patients reported various complications. Most common were transient pharmacologic side effects (n= 33), procedural (n= 5), equipment (n= 16), programming (n= 2), and psychological (n= 3). The most serious procedural complication was Staphylococcus aureus meningitis (n= 1). Catheter disconnection and leakage was noted in (n= 6) patients. Two programming errors were related to increase in drug concentration with failure to reduce the dose. Seven pumps were explanted, including three due to distorted body image. Conclusion. IDDS are effective and safe devices for pain management. The complications associated with implants are mostly pharmacological and transient.     

Initial Intrathecal Dose Titration and Predictors of Early Dose Escalation in Patients With Cancer Using a 100:1 Oral to Intrathecal Morphine Conversion Ratio

ObjectivePain is common in patients with advanced cancer, and intrathecal drug delivery (IDD) has been successfully used for recalcitrant pain. We report on our experience using a 100:1 oral-to-intrathecal morphine conversion ratio for initial dosing and factors predictive of early dose escalation.Materials and MethodsRetrospective review of an intrathecal drug delivery system (IDDS) data base at the Huntsman Cancer Institute-University of Utah in cancer patients initiated on IDD with morphine or hydromorphone. Demographic characteristics, preoperative opioid use, and initial and hospital discharge IDD settings were collected.ResultsA total of 275 patients were identified between June 2014 and May 2020. The median oral-to-intrathecal morphine conversion ratio for initial IDD dosing was 105.5:1 (interquartile range [IQR] 90–120, range 75–150). No serious adverse effects including respiratory depression or sedation were noted and the median length of stay was one night (IQR 1–2, range 1–22). Ninety-six percent of patients discontinued opioids immediately following IDDS implant. Initial IDD dosing was adequate in 42% of patients. Dose reduction was required in 4% prior to discharge due to nausea, patient request, weakness, pruritus, or urinary retention. Dose escalation was required in 54%, with a median dose increase of 66.7% (IQR 33–150%, range 5–1150%). Patients in the highest quartile of dose escalation, ≥70% between IDD initiation and discharge, had associations with younger age, higher preoperative opioid use, and inpatient status. No significant associations were found in patients who required dose reduction as compared to other patients.ConclusionsAn oral-to-intrathecal morphine conversion ratio of approximately 100:1 for initiation of IDD in patients with cancer pain was safe and well tolerated and may facilitate rapid elimination of systemic opioids. Dose reduction was rare, while a majority of patients required further dose escalation prior to discharge.     

A Clinical Evaluation of the Accuracy of an Intrathecal Drug Delivery Device

IntroductionImplantable intrathecal drug delivery (ITDD) devices are used to treat severe pain and spasticity refractory to conventional medical management. Although off-label medications and drug admixtures are commonly used in clinical practice and recommended by international guidelines, manufacturers state that this practice can result in device failure. The impact of off-label drugs and drug combinations on pump accuracy has hitherto never been assessed.Materials and MethodsA multinational, three-center, retrospective review of patient records was undertaken. The inclusion criterion was the presence of an ITDD device implantation in adult patients, with the pump in situ for the expected battery lifespan. Residual drug volumes at each refill, drug mixtures and concentrations, and rate and flow pattern of the pump (simple or flex) were recorded. A normalized flow rate ratio was calculated (actual to theoretical flow rate). The impact of nonapproved drugs, battery life, pump size, and flow program on drug delivery accuracy was assessed.ResultsData from 1402 pump refills were collected (73 patients). The overall mean accuracy ratio was 0.995 (95% CI = 0.986–1.004). The ratio for approved drug status was 0.990 vs 0.997 in nonapproved, with a difference of −0.007 (−0.032 to 0.017). At the tenth centile for remaining battery life (14 months), the ratio was 0.983 vs 1.009 for the 90th centile (69 months), with a difference of −0.026 (−0.038 to −0.014). The ratio for flex administration was 0.982 vs 1.006 for simple, with a difference of −0.024 (−0.040 to −0.008). For pump size of 40 mL, the ratio was 0.975 vs 1.010 for 20 mL, with a difference of −0.035 (−0.063 to −0.008). The 95% prediction interval for individual refill ratios was ±0.15.ConclusionIn a clinical setting, the ITDD pumps retained high levels of accuracy and acceptable precision across their lifespan despite using unapproved drugs or admixtures and under various flow modes and rates.     

North American Neuromodulation Society Educational Curriculum for Intrathecal Drug Delivery Systems Implantation and Management

ObjectivesIntrathecal drug delivery systems (IDDSs) are used for the treatment of pain and spasticity. A wide range of educational criteria exist for these devices. The North American Neuromodulation Society (NANS) Education Committee developed a comprehensive IDDS curriculum to function as a standard for physician graduate education and assessment through training and into practice.Material and MethodsA multidisciplinary and diverse task force gathered by the NANS Education Committee met in person and virtually over several sessions and developed an IDDS curriculum modeling their previous work on spinal cord stimulation and following the Accreditation Council for Graduate Medical Education (ACGME) Milestones. There were iterative revisions and adaptations to the curriculum, and the final version was approved by the NANS Board of Directors.ResultsThe curriculum was developed with distinction between implanting physicians and managing physician and physicians who perform both tasks. There is a lateral temporal progression from early learner to practitioner, with advanced learner in the middle. In addition, there is a modular vertical organization that divides the curriculum into the six educational competencies outlined by the ACGME.ConclusionA comprehensive, modular, graduated, and segmented educational curriculum for IDDSs was developed by NANS. We propose the curriculum to be the standard for guidance and assessment of trainees and physicians pursuing training in implanting or managing IDDSs.     

Perceived Success and Failure of Intrathecal Infusion Pump Implantation in Chronic Pain Patients

Objectives. Over the past few years, there has been an increased reliance on the intrathecal delivery of drugs for patients suffering from intractable pain. We sought to demonstrate the effectiveness of the intrathecal pain pump by examining self‐reported pre‐ and postimplantation pain levels. Methods. Eighty‐four patients who had elected to implant a Medtronic SynchroMed 1 or 2 system in order to control their pain were asked to complete a survey. The survey consisted of pain ratings before implantation, pain ratings postimplantation, medications used before and after implantation, and patient satisfaction with the procedure. Results. Perceived success rate for implantation is 68%, when measured by the ability to reduce reliance on oral medication. When measured by willingness to undergo the procedure again, the success rate is 86%. Conclusions. Overall, the implantation of an intrathecal pain pump is an effective way for most people to manage their intractable pain and reduce reliance on oral medications.