Howard S. Smith

Implications of Opioid Analgesia for Medically Complicated Patients

Opioid analgesics have an established role in the management of postoperative pain and cancer pain, and are gaining acceptance for the management of moderate to severe chronic noncancer pain, most notably chronic low back pain and osteoarthritis, that does not respond to other interventions. Many patients with chronic pain have co-morbid medical conditions that may complicate opioid therapy. Selecting the appropriate opioid requires knowledge of how individual opioids differ with respect to metabolism and interaction with concurrent medications, as well as the reasons why specific medical conditions may influence their efficacy and tolerability. Polypharmacy is a common complicating condition in the elderly and in patients with psychiatric illness, cancer, cardiovascular disease, diabetes mellitus or other chronic illnesses. Polypharmacy, though often necessary for patients with multiple medical conditions, also multiplies the risk of drug interactions. Pharmacokinetic drug interactions can increase or reduce exposure to the opioid or concurrent medications, reducing efficacy and/or tolerability and increasing toxicity. Pharmacodynamic interactions can enhance the depressive effects of opioids, compromising safety. Patients with impaired renal or hepatic function may have difficulty clearing or metabolizing opioids and concurrent medications, leading to increased risk of adverse events. Patients with cardiovascular, cerebrovascular or respiratory disease (including smokers of ≥2 packs/day with no other diagnosis) may be more susceptible to respiratory depression, bradycardia and hypotension with any opioid, and a few specific opioids pose additional risks. Patients with cerebrovascular disease, dementia, brain injury or psychiatric illness are more susceptible to opioid effects on the CNS, which can include euphoria, cognitive impairment and sedation. Appropriate opioid selection may mitigate these effects. Even in older patients, addiction, abuse and misdirection of prescribed opioids are of concern. Higher risk exists for patients with psychiatric illness, history of substance abuse, and identifiable substance abuse risk factors. Screening for abuse potential and vigilant patient monitoring should be routine. Opioids differ in their ability to produce euphoria, based on opioid receptor agonism, but substance abusers may be more influenced by availability, familiarity and cost factors. Consequently, opioid selection has limited influence on abuse potential but can facilitate ease of monitoring. This review provides an overview of opioid use in medically complicated patients and recommendations on how to optimize analgesia while avoiding adverse events and drug interactions in the clinical setting. Articles cited in this review were identified via a search of EMBASE and PubMed. Articles selected for inclusion discussed characteristics of specific opioids and general physiological aspects of opioid therapy in important patient populations.

Botulinum toxins: mechanisms of action, antinociception and clinical applications.

Botulinum toxin (BoNT) is a potent neurotoxin that is produced by the gram-positive, spore-forming, anaerobic bacterium, Clostridum botulinum. There are 7 known immunologically distinct serotypes of BoNT: types A, B, C1, D, E, F, and G. Clostridum neurotoxins are produced as a single inactive polypeptide chain of 150kDa, which is cleaved by tissue proteinases into an active di-chain molecule: a heavy chain (H) of ∼100 kDa and a light chain (L) of ∼50 kDa held together by a single disulfide bond. Each serotype demonstrates its own varied mechanisms of action and duration of effect. The heavy chain of each BoNT serotype binds to its specific neuronal ecto-acceptor, whereby, membrane translocation and endocytosis by intracellular synaptic vesicles occurs. The light chain acts to cleave SNAP-25, which inhibits synaptic exocytosis, and therefore, disables neural transmission. The action of BoNT to block the release of acetylcholine botulinum toxin at the neuromuscular junction is best understood, however, most experts acknowledge that this effect alone appears inadequate to explain the entirety of the neurotoxins apparent analgesic activity. Consequently, scientific and clinical evidence has emerged that suggests multiple antinociceptive mechanisms for botulinum toxins in a variety of painful disorders, including: chronic musculoskeletal, neurological, pelvic, perineal, osteoarticular, and some headache conditions.

Perioperative Intravenous Acetaminophen and NSAIDs

BACKGROUND Unrelieved postoperative pain may result in pain/suffering, as well as multiple physiological and psychological consequences (e.g., splinting, impaired gastrointestinal motility/ileus, and impaired wound healing) which may adversely affect perioperative outcomes and contribute to increased length of stay. Multimodal or balanced analgesia, utilizing regional analgesic techniques (where possible) and nonopioid analgesics appear to represent a viable strategy to decrease systemic opioid consumption and improve postoperative analgesia. The use of multimodal analgesic strategies may result in reduced frequency and severity of unwanted opioid-related adverse effects, better clinically meaningful pain relief, diminished opioid consumption, and an overall improvement of patient satisfaction as well as health outcomes (e.g., earlier ambulation and discharge). OBJECTIVES Review key aspects of intravenous (i.v.) acetaminophen (APAP) use in the postoperative setting. DESIGN Focused literature review. RESULTS Intravenous APAP is safe, effective for mild-to-moderate postoperative pain, well-tolerated, and has a very favorable side effect profile with no clearly demonstrated clinically significant drug-drug interactions. It does not exhibit any significant effects on platelet aggregation and therefore may be the preferred nonopioid analgesic when surgical bleeding is an issue. CONCLUSION The i.v. formulation of APAP represents a safe and effective first-line analgesic agent for the treatment of acute mild-to-moderate pain in the perioperative setting when oral agents may be impractical or when rapid onset with predictable therapeutic dosing is required.

Safety and efficacy of intrathecal ziconotide in the management of severe chronic pain

Ziconotide is a conopeptide intrathecal (IT) analgesic which is approved by the US Food and Drug Administration (FDA) for the management of severe chronic pain. It is a synthetic equivalent of a naturally occurring conopeptide found in the venom of the fish-eating marine cone snail and provides analgesia via binding to N-type voltage-sensitive calcium channels in the spinal cord. As ziconotide is a peptide, it is expected to be completely degraded by endopeptidases and exopeptidases (Phase I hydrolytic enzymes) widely located throughout the body, and not by other Phase I biotransformation processes (including the cytochrome P450 system) or by Phase II conjugation reactions. Thus, IT administration, low plasma ziconotide concentrations, and metabolism by ubiquitous peptidases make metabolic interactions of other drugs with ziconotide unlikely. Side effects of ziconotide which tend to occur more commonly at higher doses may include: nausea, vomiting, confusion, postural hypotension, abnormal gait, urinary retention, nystagmus/amblyopia, drowsiness/somnolence (reduced level of consciousness), dizziness or lightheadedness, weakness, visual problems (eg, double vision), elevation of serum creatine kinase, or vestibular side effects. Initially, when ziconotide was first administered to human subjects, titration schedules were overly aggressive and led to an abundance of adverse effects. Subsequently, clinicians have gained appreciation for ziconotide’s relatively narrow therapeutic window. With appropriate usage multiple studies have shown ziconotide to be a safe and effective intrathecal analgesic alone or in combination with other intrathecal analgesics.

Botulinum toxin in pain management of soft tissue syndromes

Abstract: Botulinum toxin is approved for the treatment of muscle overactivity associated with several disorders, such as dystonias. However, control of muscle spasm often results in pain relief as well. Effective relief of pain associated with myofascial pain syndrome provides a model for the use of botulinum toxin to relieve pain associated with other types of soft‐tissue syndromes, such as fibromyalgia. Although the mechanisms that trigger the pain in these syndromes vary, recent data suggest that a central neuroplastic mechanism may contribute to many complex pain syndromes. Botulinum toxin therapy may be particularly useful in soft‐tissue syndromes that are refractory to traditional treatment with physical therapy, electrical muscle stimulation, and other approaches. Although not used as first‐line therapy for pain relief, botulinum toxin may decrease pain long enough for patients to resume more conservative therapy. A primary benefit of treatment with botulinum toxin is its long duration of action. Several studies have demonstrated the efficacy of botulinum toxin types A and B in treating several neuropathic pain disorders. Proper patient selection, injection technique, and dosing are critical to obtaining the best outcomes in managing pain with botulinum toxin. Additional study is needed to better characterize its use for the treatment of pain.

The metabolism of opioid agents and the clinical impact of their active metabolites.

BackgroundThe metabolism of opioids is critical to consider for multiple reasons. The most commonly prescribed opioid agents often have metabolites that are active and are the source of both analgesic activity and an increased incidence of adverse events. Many opioids are metabolized by cytochrome P450 enzymes. Polymorphisms in cytochrome P450 genes and inhibition or induction of cytochrome P450 enzymes by coadministered drugs may significantly impact the systemic concentration of opioids and their metabolites and the associated efficacy or adverse events. MethodsThis is a narrative review of the metabolism of various opioids that will highlight the impact of their active metabolites, and the potential impact of cytochrome P450 activity on analgesic activity. ResultsAn understanding of “opioid metabolic machinery,” cytochrome P450 activity, and drug-drug interactions in the context of opioid selection may benefit clinicians and patients alike. ConclusionsA greater appreciation of the metabolism of commonly prescribed opioid analgesics and the impact of their active metabolites on efficacy and safety may aid prescribers in tailoring care for optimal outcomes.

Explosive growth of facet joint interventions in the medicare population in the United States: a comparative evaluation of 1997, 2002, and 2006 data

BackgroundThe Office of Inspector General of the Department of Health and Human Services (OIG-DHHS) issued a report which showed explosive growth and also raised questions of lack of medical necessity and/or indications for facet joint injection services in 2006.The purpose of the study was to determine trends of frequency and cost of facet joint interventions in managing spinal pain.MethodsThis analysis was performed to determine trends of frequency and cost of facet jointInterventions in managing spinal pain, utilizing the annual 5% national sample of the Centers forMedicare and Medicaid Services (CMS) for 1997, 2002, and 2006.Outcome measures included overall characteristics of Medicare beneficiaries receiving facet joint interventions, utilization of facet joint interventions by place of service, by specialty, reimbursement characteristics, and other variables.ResultsFrom 1997 to 2006, the number of patients receiving facet joint interventions per 100,000Medicare population increased 386%, facet joint visits increased 446%, and facet joint interventions increased 543%. The increases were higher in patients aged less than 65 years compared to those 65 or older with patients increasing 504% vs. 355%, visits increasing 587% vs. 404%, and services increasing 683% vs. 498%.Total expenditures for facet joint interventions in the Medicare population increased from over

Opioid induced nausea and vomiting.

229 million in 2002 to over

Alpha2 receptors and agonists in pain management

511 million in 2006, with an overall increase of 123%. In 2006, there was a 26.8-fold difference in utilization of facet joint intervention services in Florida compared to the state with the lowest utilization - Hawaii.There was an annual increase of 277.3% in the utilization of facet joint interventions by general physicians, whereas a 99.5% annual increase was seen for nurse practitioners (NPs) and certified registered nurse anesthetists (CRNAs) from 2002 to 2006. Further, in Florida, 47% of facet joint interventions were performed by general physicians.ConclusionsThe reported explosive growth of facet joint interventions in managing spinal pain in certain regions and by certain specialties may result in increased regulations and scrutiny with reduced access.

Painful hidradenitis suppurativa.

Opioids are broad spectrum analgesics that are an integral part of the therapeutic armamentarium to combat pain in the palliative care population. Unfortunately, among the adverse effects of opioids that may be experienced along with analgesia is nausea, vomiting, and/or retching. Although it is conceivable that in the future, using combination agents (opioids combined with agents which may nullify emetic effects), currently nausea/vomiting remains a significant issue for certain patients. However, there exists potential current strategies that may be useful in efforts to diminish the frequency and/or intensity of opioid-induced nausea/vomiting (OINV).