Abstract
Intrathecal drug delivery has been a valuable treatment for severe refractory pain conditions. However, despite the growing evidence about and success of implanted drug delivery, limitations such as variations in clinical practices exist. Fortunately clinical practice guidelines, such as the Polyanalgesic Consensus Conference recommendations, provide appropriate care based on the best available scientific evidence and broad consensus.
Keywords
Intractable pain, Intraspinal drug delivery, IT drug delivery, Pain management, Polyanalgesic Consensus Conference, Practice guidelines
Introduction
The use of intrathecal (IT) therapies for the control of chronic pain has become an important part of the treatment algorithm for those who suffer with chronic disease. In the effort to control suffering, these therapies have been used in different clinical settings with varying degrees of success. The approval of IT morphine by the United States Food and Drug Administration (FDA) led to the application of chronic infusions through implanted drug delivery (IDD) systems for treatment of pain, but also to physician choices of other agents to treat pain when IT morphine was unsuccessful or created side-effects that made this therapy a poor option. With the advent of new therapy ideas, the need for guidance for this new therapy became important among clinicians offering IT options. The development of IT consensus guidelines was born out of the necessity to improve efficacy and safety for this select patient population. To understand the need for this guidance we must first consider the role of IT agents from the initial research to current times.
Endogenous opiate activity is known to elevate the perception of nociceptive pain ( ). Mammalian radioisotope studies have been shown that the distribution of opiate receptors (ORs) in the central nervous system (CNS) is conserved between humans and primates and not uniformly distributed. The limbic cortex (amygdala, hippocampus), hypothalamus, caudate nucleus, and periaqueductal gray matter appear to be preferred sites for ORs ( ). These ORs are independent of cholinergic and noradrenergic pathways ( ) and have a 10-fold to 100-fold greater affinity for opiate antagonists than agonists ( ). Furthermore, activation of ORs present at the spinal cord level (substantia gelatinosa) can mediate spinal reflexes to noxious stimuli ( ). Endogenous opiate peptides bind to ORs to modulate responses to pain ( ), and can be found throughout the cerebral spinal fluid ( ).
Chronic catheterization of the IT space has been shown to be well tolerated in mammals, with distribution of drugs demonstrating limited cephalad or caudad spread from the catheter tip ( ). IT morphine ( ) and baclofen ( ) are known to affect spinal cord activity in animal models through independent spinal cord pathways ( ), and chronic catheterization and dosing of these agents showed no effect on vital signs, motor function, or higher CNS function ( ).
published some of the earliest data on the use of IT morphine in humans. IT morphine was profoundly effective in providing relief in patients suffering from intractable pain secondary to cancer-related disease states. In this preliminary observational study, six of eight patients demonstrated profound analgesia following single IT dosing of morphine without evidence of significant side-effects, leading to the notion that persistent IT dosing via catheter placement could be an effective means to control intractable pain ( ).
Meanwhile, several other longitudinal studies suggested that epidural morphine was effective for the treatment of both acute and chronic pain of ischemic and musculoskeletal origin ( ) and cancer-related pain ( ), but significantly less effective for pain related to labor or with a strong neuropathic component ( ).
Although the efficacy of intraspinal opiates had been proven, the ability to provide continuous relief was hindered by early reports of respiratory complications associated with IT administration and later epidural administration ( ). However, published a case series demonstrating the successful use of an implanted epidural Holter-Broviac assembly in two patients, one of whom was also implanted with a Silastic morphine reservoir. These studies provided a significant early foundation for the development and use of the Infusaid, a percutaneously refillable implanted drug reservoir for the delivery of continuous epidural morphine for the treatment of cancer-related pain ( ).
The placement of infusion catheters into the epidural space was grounded mainly in the fear of CNS complications, primarily cerebral spinal fluid leak, hygroma, and meningitis. Many clinicians assumed that the epidural route would be a safer option based on these issues. However, in at least one study the use of IT drug delivery by implanted continuous delivery systems demonstrated less pain for longer periods when compared to patients with epidural catheters. IT placement was not associated with anatomic, infectious, or cardiopulmonary-related comorbidities ( ).
Soon thereafter reports emerged evaluating IDD using baclofen for spasm-related diseases ( ) and local anesthetic alternatives to morphine in the canine model ( ).
The use of intraspinal opiates represented a significantly efficacious advancement for the treatment of intractable pain, and there was considerable interest in providing consensus for patient selection ( ) and best clinical practices ( ). Initial recommendations of patient selection primarily focused on the presence of a successful intraspinal opiate trial with clear pain relief and tolerance to, or absence of, any adverse uncontrolled medication side-effects. Predominant patient selection criteria included psychosocial stability, surgical candidacy, failure of definitive treatment options, and life expectancy ( ). Failure of systemic opiates as well as the predominance of nociceptive rather than neuropathic pain predicated the use of IDD ( ). While the use of intraspinal delivery was generally more liberal for a patient with malignant pain, an early precursor to current guidelines suggested that other less-invasive procedures should be considered first, and IT drug delivery be used de ultimo ( ).
Despite the growing evidence and success of IT therapy as an advanced interventional treatment modality for severe chronic pain, obstacles such as poor patient selection, safety concerns, suboptimal training, and, most importantly, variations in clinical practices led to underutilization.
In medicine, clinical practice guidelines are systematically developed statements to assist practitioner and patient decisions regarding appropriate healthcare for specific circumstances. They describe appropriate care based on the best available scientific evidence and broad consensus, reduce inappropriate variation in practice, and highlight shortcomings of existing relevant literature and suggest appropriate future research.
PACC 2000
In an effort to create standardized clinical guidelines for intraspinal analgesia, the first Polyanalgesic Consensus Conference (PACC) was held in 1999, attended by well-known experts in the field of opioid delivery ( ). The meeting was funded by a collaboration, Medtronic (Minneapolis, Minnesota), the primary supplier of implantable IT IDD systems at the time. PACC 2000 was planned to be the first of a recurring series of conferences that would strive to improve outcomes for both safety and efficacy in the complex and growing field of intraspinal drug administration. The PACC panel consisted of experts with either extensive clinical experience, expertise in basic science research and clinical studies, or expertise in evidence assessment or publication. The leaders of the project strived to choose members based on their publication history, work in the area of research, and patient care. The goal of creating a diverse group with extensive knowledge of the field was balanced by diversity across specialties and geography. Four articles were published in the Journal of Pain and Symptom Management (Portenoy, editor), covering survey results of clinical practice, evidence review of IT delivery of pain medication, clinical guidelines for IDD, and discussion of future directions for the management of pain by IDD.
To understand better the landscape of practice at the time, a survey was conducted to evaluate clinical conduct by practicing physicians utilizing implantable IT drug delivery in the United States and the international community. The survey included over 400 physicians treating over 13,000 patients ( ). The results revealed that morphine was the principal opioid agent used for IDD, followed by hydromorphone. Bupivacaine was the primary local anesthetic agent used, most frequently in combination with morphine. Although most physicians used morphine, other drugs were also selected, and without clear indications. The survey results showed that there was significant variation in practice, supporting the need for clinical guidelines.
In addition to the survey paper, an evaluation of IT drug options was performed to give a better understanding of safety for IDD. This review included both animal and human studies, with a search strategy that included basic science and clinical practice. Each drug was evaluated for safety and efficacy. The review of literature on IT delivery of pain medication supported the safety of IT morphine, with favorable efficacy and acceptable human and animal safety data ( ). The review also revealed that despite the widespread acceptance and use by many clinical practices, there was a need for additional controlled studies to give further support to the safety and efficacy of agents used in IT infusions. The consensus group called for extensive future research for morphine and other agents that were being used with little basic science or animal toxicology data to support their use.
The consensus guidelines were based on systematic reviews, evidence scoring, and clinical experiences ( ). The panel evaluated existing literature and provided initial structure for clinical decision-making that was based on the best available evidence in the literature, the perspectives of the experienced clinicians in the panel for drug selection, and factors affecting medical decision-making. When evidence was lacking, the goal of the consensus panel was to consider the clinical experiences of expert physicians and make best-practice decisions and recommendations to fill in the scientific gaps. With this process, the panel made recommendations that were important for the practice of medicine regarding the safe and efficacious use of IDD.
Single-agent use of morphine was considered by the panel to be a first-line agent, at 0.1–20 mg/day with 1–3 month refills. The guidelines also provided recommendations for second-line to fourth-line agents, evaluation of therapeutic failure, and IDD dosing. These guides are seen in Table 70.1 .
In the fourth published paper of PACC 2000, the committee called for an effort to improve and enhance the evidence. Based on the deficiencies identified in the main PACC consensus paper, the panel created a paper that defined the need for future scientific endeavors. This led to a roadmap for bench and clinical research planning for the next 2 decades. This guidance for IT research was published as a separate paper for consideration of research, but also was a good snapshot of the lack of knowledge in many of the unresolved questions of the time in regard to IDD ( ).
PACC 2003
At the time of the publication of the 2000 guidance, the committee called for an ongoing process to update the field with new recommendations. That commitment was accomplished in 2003. Due to rapid changes in the science and practice of IDD, PACC 2003 was organized to address and update the medical literature, update the algorithm for intraspinal drug selection, propose guidelines for optimizing drug concentration and dosages, develop consensus regarding the evidence required to support use of a drug for long-term IT infusion, and clarify existing regulations pertaining to the use of compounding drugs for IT administration ( ).
PACC 2003 first addressed the causal relationship between IT morphine sulfate infusion and the formation of catheter-tip inflammatory masses, called IT granulomas. Using a best-evidence approach, the panel updated the algorithm and recommended that hydromorphone be included with morphine as first-line agents for IDD. Additionally, the panel recommended maximum IT dosages and concentrations for morphine, hydromorphone, bupivacaine, and clonidine. Finally ziconotide, previously known as SNX-111, a neuronal-specific calcium channel blocker, was first mentioned as a potential IT drug agent. The changes in drug and safety recommendations in the 2003 version of the PACC guidance significantly impacted the field and were a major attempt to improve safety and reduce the impact of IT granuloma on spinal cord injury. Also the guidance of using ziconotide was helpful in providing a possible nonopioid, besides bupivacaine, in the armory of IT drug options. At that time ziconotide was not approved for use in the United States or the European Community, and its use and recommendations were based solely on scientific study. Because of this lack of clearance the panel did not place the agent within the algorithm, but stated that it could be placed in the algorithm based on the results of an impending pivotal multicenter study ( ). See Table 70.2 for PACC 2003 guidelines.
PACC 2007
The third PACC was held in 2007, and for the first time the PACC guidance was published in Neuromodulation: Technology at the Neural Interface, Journal of the International Neuromodulation Society ( ). Also the term intraspinal was replaced with intrathecal, since the preponderance of spinal catheters for IDD systems were IT. The panel reviewed the 2000 and 2003 conclusions and guidelines and provided an update of the IT drug infusion guidelines. Additionally, recommendations were made for the role of IT therapies for end-of-life care. The 2007 PACC algorithm included ziconotide, along with morphine and hydromorphone, as a first-line agent for IT therapies, since ziconotide was now commercialized as Prialt and FDA approved. The panel also addressed the potential hormonal adverse effects of IT analgesics, particularly opioid medications, and gave guidance for the recognition and treatment of new potential systemic effects of these IT agents ( Table 70.3 ).
PACC 2012
In accordance with the recommendations made more than a decade earlier, PACC reconvened in 2011 with the goal of reviewing and updating the significant and profound new knowledge that was available in the field of IT drug delivery and providing the most comprehensive and detailed guidance to date ( ). For the first time, in this new iteration of the PACC the panel recommended a change in the way IT therapies were used: prior to selecting an IT agent, the clinician should assess whether the patient being treated had predominantly a neuropathic, nociceptive, or mixed pain type. PACC 2012 then included separate guidance for IT therapy for neuropathic, nociceptive, and mixed pain syndromes, based on the evidence in different clinical settings.
The guidelines also specifically addressed catheter-tip IT granuloma ( ), previously discussed in 2003. The 2012 guidance examined the FDA reporting on granuloma and changed the guidance on drug concentration and dosing. In addition to guidance on preventing IT granuloma, PACC 2012 gave other recommendations to reduce morbidity and mortality of the therapy.
In the 2012 PACC guidelines the panel gave specific recommendations for trialing patients for IDD systems, to standardize clinical selection processes further. Specifically, PACC 2012 provided discussions and recommendations for patient risk stratification, prevention of granuloma, screening, detection, and diagnosis and treatment of IT granuloma. Recommendations for the reduction of morbidity and mortality provided best-practice guidelines to improve patient care and outcomes for IT infusions. Areas of focus included respiratory depression, infection, granuloma, device-related complications, endocrinopathies, and human error ( ). PACC 2012 recommended morphine, ziconotide, and morphine plus bupivacaine as first-line agents for neuropathic pain, while fentanyl, morphine, hydromorphone, and ziconotide were listed as first-line agents for nociceptive pain—see Tables 70.4 and 70.5 ( ). Finally, the panel provided discussion and recommendations for IT drug trialing that included goals, methods, medications, and management, as well as retrialing for IT drug delivery ( ).
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