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 Administration of Different Drugs by Programmable Infusion Device in Chronic Pain. A Case Report.

Objective and Importance . The subarachnoid infusion of narcotics by programmable devices in patients with chronic non-malignant pain can be a useful therapeutic method. However, certain side-effects, opioid tolerance or changes in the nature of the pain can lead to failure of the therapy. Clinical Presentation . We present a case report of a woman with both chronic perineal pain and sciatic pain with radiation to her lower limbs caused by failed back surgery syndrome. The pain proved to be resistant to common medical therapy and to spinal cord stimulation. Technique . After surgical implantation of a programmable infusion pump, the patient's leg pain improved with an intrathecal infusion of morphine and bupivacaine. The perineal pain was treated with an infusion of clonidine. The patient therefore needed alternative infusions of both drugs with changes of infusional parameters. Conclusion . The possibility of varying the infusion method of mixed drugs or alternating the drugs is fundamental for successful therapy since neuropathic pain must be considered a dynamic state.     

Association Between Oral Pain Medications and Intrathecal Opioid Dose Escalation: A Retrospective Analysis

ObjectivesPatients treated with intrathecal therapy frequently require opioid dose increases to maintain analgesia. The kinetics of intrathecal opioid dose escalation are poorly understood. We hypothesized that antidepressant use, antiepileptic use, and lower baseline oral opioid intake prior to intrathecal pump implantation will be protective against intrathecal opioid dose escalation.Materials and MethodsTargeted drug delivery medication doses were collected from patients who had an intrathecal pump implanted between 2007 and 2016. From a sample size of 136 patients, the association between antidepressant, antiepileptic, and oral opioid use with intrathecal dose escalation was assessed using statistical models.ResultsIndividuals using an antiepileptic had an estimated ratio of means (97.5% CI) of opioid consumption of 0.91 (97.5% CI: [0.48, 1.73], p = 0.74) at six months, 0.83 ([0.43, 1.58], p = 0.51) at 12 months, and 0.77 ([0.40, 1.45], p = 0.36) at 24 months. Patients prescribed antidepressants had an estimated ratio of means (97.5% CI) of 1.43 ([0.77, 2.65], p = 0.19) at six months, 1.41 ([0.76, 2.63], p = 0.22) at 12 months, and 1.33 ([0.70, 2.51], p = 0.31) at 24 months. In our secondary analysis of pre-implant oral opioid use, patients treated with high oral opioid doses had a similar pattern of intrathecal dose escalation when compared to patients using low doses of oral opioids.ConclusionsUse of antiepileptics, antidepressants, or low oral opioid doses was not associated with attenuation of intrathecal dose escalation. Intrathecal opioid dose escalation was observed to occur similarly, regardless of baseline oral analgesics concomitantly employed.     

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.     

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.     

Intrapleural Migration of a Spinal Catheter in a Patient With Arachnoiditis and Extensive Epidural Scarring After Tethered Cord Release: A Case Report and Review of Literature

Objective: The objective of this study was to report a case of new onset refractory pain from intrapleural migration of a spinal catheter five months after the implantation of an intrathecal drug delivery system (IDDS). Materials and Methods: A 57‐year‐old man had intractable pain because of multiple intradural spinal explorations for tethered cord release. His pain was effectively treated with intrathecal morphine via an IDDS. Five months after the implantation, the patient developed return of the original pain more than two weeks after intrapleural migration of the intrathecal catheter. Results: The migration was documented by computed tomography, and repositioning of the catheter rendered the patient comfortable. The gradual onset of pain may have been due to decreasing delivery of drug to the cerebrospinal fluid as the catheter tip migrated further away from the dura. To our knowledge, this complication has not been reported in the literature. Conclusion: Physicians and nursing staff that place and manage an IDDS should be aware of this complication.     

Symptomatic Intrathecal Catheter Tip Granuloma Formation With Ultralow-Dose and Low-Concentration Morphine Infusion: A Case Report and Review of Literature

ObjectivesThis study aimed to describe catheter tip granuloma (CTG) formation in a patient on ultralow-dose, low-concentration morphine via intrathecal (IT) drug delivery system (IDDS) and to review literature for reports of IT granuloma formation and association with drug type, drug dose, and drug concentration.Materials and MethodsThis review describes diagnosis and management of a patient with CTG on ultralow-dose, low-concentration morphine. PubMed data base search was conducted from January 1990 to July 2021 for original articles on CTG formation in humans getting intrathecal analgesics. Data were extracted on indications for IDDS, time to detect CTG, and type of drug/s with drug doses and concentrations. Percentages and average with range for age, sex, duration of infusion, drug doses, and drug concentrations were calculated.ResultsWe describe CTG formation and spinal cord compression with worsening of sensorimotor deficits in a patient receiving intrathecal morphine at ultralow dose (0.6 mg/d) and low concentration (1.2 mg/mL), which is the lowest reported morphine dose associated with CTG in the literature. Our literature review shows all IT drugs have the potential for granuloma formation, and there is no drug with granuloma-inhibiting effect.ConclusionsThere is no drug, dose, or concentration that has granuloma-sparing effect. It is imperative to maintain vigilance for potential CTG in all patients with IDDS. Routine monitoring and prompt evaluation for any unexplained symptoms or change in neurologic status from baseline is critical in early detection and treatment of CTG.