In the ambulatory surgical setting, it is beneficial to have the analgesic efficacy of opioids, whereas minimizing or eliminating the conventional opioid side effects that often result in prolongation of PACU stay or readmission. Difelikefalin or CR-845 (Cara Therapeutics, Stamford, Connecticut, USA), is a κ-receptor agonist. By avoiding the conventional μ-receptor group, the incidence of the central side effects of opioid agonism are mitigated.
The κ receptors are agonized at the peripheral nerves, avoiding undesirable effects leading to increased healthcare interventions and abuse potential such as respiratory depression, nausea and vomiting, and euphoria. In completed phase 2 trials (www.caratherapeutics.com), the CR-845 group resulted in a statistically significant reduction in pain intensity as measured by AUC utilizing the numerical rating scale collected over the first 24 h postop in patients who underwent inguinal hernia surgery and hysterectomy. Interestingly, there was also a statistically significant reduction in the incidence of PONV, need for rescue pain medication, and improvement in patient global assessment 24 h after surgery versus placebo. Adverse events including aquaresis (the diuretic loss of free water without electrolyte loss) in a dose-dependent fashion were observed. It is currently undergoing phase 3 trials.
To further examine ways to find analgesic treatments that can be used on outpatient basis, sufentanil has garnered attention because it has rapid equilibration between the plasma and CNS, on the order of just several minutes. This allows for greater titratability with quicker onset and longer duration of action, without the need for intravenous access, thereby facilitating use in an outpatient setting. In a dose-finding study by Singla et al. [57▪] in bunionectomy patients, sublingual sufentanil (Zalviso) when administered as a onetime 30 mcg dose had a significant prolongation on time to first rescue analgesic when compared with morphine, with fewer adverse events. A manufacturer programmed dispenser of 15 mcg nanotablets with a 20 min lockout was studied by Scardino et al. , where patients who underwent total knee replacements were placed on a fast-track program that utilized a multimodal analgesic regimen. They found that the patients with the conventional femoral nerve block-based regimen reported lower pain scores throughout the 3 day study period; the group whose pain was treated by sublingual fentanyl reported lower movement-evoked pain scores throughout the same test period. Of note, by taking the programming away from the caregivers and patients, the Zalviso dispenser device (AcelRx Pharmaceuticals, Redwood City, California, USA) appears to avoid a number of issues relating to abuse and overdose.
Of the opioid drugs studied, inhaled fentanyl appears to be the most consistent in terms of bioavailability. The Staccato Fentanyl for Inhalation device (Alexza Pharmaceuticals Inc., Mountain View, California, USA) was demonstrated by Macleod et al.  to provide similar peak arterial concentrations of fentanyl for inhaled and intravenous administration. Similar to the sublingual sufentanil administration, this provided a potential means by which opioids can be administered in a controlled manner, without the need for intravenous access. Intranasal fentanyl has been studied in the setting of procedural sedation in the emergency department setting. [60▪,61]. In a prospective, randomized, single-blind noninferiority trial, intranasal fentanyl was shown to be superior to intravenous (i.v.) morphine in reducing pain and distress during bedside incision and drainage procedures as measured by the Observational Scale of Behavioral Distress-Revised (OSBD-R) scores. However, this study was small, and therefore of limited clinical utility. Interestingly, in a study that relied on a questionnaire of woman who received intranasal fentanyl versus subcutaneous fentanyl or intramuscular pethidine for labor analgesia, the women who received intranasal fentanyl had the highest satisfaction scores. In fact, some were quoted as stating they would choose to deliver in a center that provided it over the other routes of administration .
The utilization of older drugs which found some use for analgesia has included the α-2 agonist family of drugs. α-2 adrenergic receptors are thought to lie in the locus coeruleus , thereby reducing neural throughput along the posterior horn of the spinal cord. There are also α-2 receptors placed presynaptically, inhibiting release of norepinephrine thereby, inhibiting pain signal transmission in the brain. Dexmedetomidine, particularly, is thought to promote the release of acetylcholine along spinal internuerons, possibly contributing to the release of nitric oxide, which may help modulate analgesia. The use of intranasal dexmedetomidine is supported in the literature for use in pediatric sedation and analgesia . For specific FDA approval for periprocedural pain, Dex-IN (RECRO Pharma, Malvern, Pennsylvania, USA) is a formulation that has undergone phase 2 testing. In a multicenter, double-blind, placebo-controlled study of patients who underwent bunionectomy, the study groups were allowed to receive either the intranasal dexmedetomidine or placebo every 6 h starting on postop day 1. Thus far, the drug has shown its potential efficacy as an analgesic as it demonstrated a significant summed pain intensity difference score after 48 h (SPID48) versus placebo. The study also noted the need for rescue analgesia, adverse events, and SPID48 scores over various times intervals. The adverse events included nasal discomfort, hypotension, and bradycardia.
A strategy of slow-release of dexmedetomidine has been tested via a transdermal patch. TPU-006 (Teikoku Pharma, San Jose, California, USA) is a transdermal system that is based on what has been used for transdermal lidocaine patches. It is intended to dispense the dexmedetomidine over 3 days when applied in the immediate postsurgical period. In a phase 2 double-blind proof-of-concept study, patients who underwent bunionectomy were given either test drug or placebo. The test group had lower pain scores, reduced need for opioid rescue over 3 days, and less constipation and nausea with no increase in sedation.
The current and forthcoming strategies for analgesic management in the ambulatory setting employ two broad strategies: improving the analgesic effects of conventional medications that are already components of multimodal analgesic regimens using drug delivery vehicles that take advantage of established efficacy while trying to reduce their undesirable systemic side-effects and formulation of newer drugs that utilize the improved understanding of the intracellular pathways involved in pain transmission and modulation. As the metrics for determining efficacy of different analgesic regimens differ from one another, it may be challenging to develop direct comparisons in the context of ERP. Acceptance of specific accepted standards of efficacy may contribute to more direct comparisons and thus, greater conformity across different ambulatory analgesic protocols.
Papers of particular interest, published within the annual period of review, have been highlighted as:
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