Review of naloxone safety for opioid overdose: practical considerations for new technology and expanded public access.

Opioid overdose and mortality have increased at an alarming rate prompting new public health initiatives to reduce drug poisoning. One initiative is to expand access to the opioid antidote naloxone. Naloxone has a long history of safe and effective use by organized healthcare systems and providers in the treatment of opioid overdose by paramedics/emergency medicine technicians, emergency medicine physicians and anesthesiologists. The safety of naloxone in a prehospital setting administered by nonhealthcare professionals has not been formally established but will likely parallel medically supervised experiences. Naloxone dose and route of administration can produce variable intensity of potential adverse reactions and opioid withdrawal symptoms: intravenous administration and higher doses produce more adverse events and more severe withdrawal symptoms in those individuals who are opioid dependent. More serious adverse reactions after naloxone administration occur rarely and may be confounded by the effects of other co-intoxicants and the effects of prolonged hypoxia. One component of the new opioid harm reduction initiative is to expand naloxone access to high-risk individuals (addicts, abusers, or patients taking high-dose or extended-release opioids for pain) and their close family or household contacts. Patients or their close contacts receive a naloxone prescription to have the medication on their person or in the home for use during an emergency. Contacts are trained on overdose recognition, rescue breathing and administration of naloxone by intramuscular injection or nasal spraying of the injection prior to the arrival of emergency medical personnel. The safety profile of naloxone in traditional medical use must be considered in this new context of outpatient prescribing, dispensing and treatment of overdose prior to paramedic arrival. New naloxone delivery products are being developed for this prehospital application of naloxone in treatment of opioid overdose and prevention of opioid-induced mortality.

Intranasal naloxone administration for treatment of opioid overdose.

PURPOSE: The pharmacology, pharmaco-kinetic properties, and clinical efficacy of naloxone injection administered intranasally for the reversal of opioid overdose are reviewed. SUMMARY: Naloxone is an opioid-receptor antagonist that is used in the treatment of opioid overdose to reverse the respiratory and central nervous system-depressant effects of the opioid. Naloxone injection is traditionally given by intravenous, intramuscular, and subcutaneous routes. Paramedics also administer naloxone injection intranasally in the prehospital setting to treat suspected opioid overdose. The nasal mucosa has a rich blood supply that allows for efficient drug absorption and the avoidance of first-pass hepatic metabolism that would be seen with oral administration. Obtaining vascular access can be difficult in known drug users, prolonging the time required to administer the antidote. Patients awakening from an overdose may be agitated, confused, and even combative, thus increasing the risk of needle-stick injury to first responders. The intranasal route avoids the need for establishing vascular access and can be associated with speedier patient recovery. In two randomized controlled trials, intranasal naloxone alone was shown to be sufficient for reversing opioid-induced respiratory depression in 74% and 72% of the respective study populations of patients experiencing opioid overdose. In addition, the safety profile of intranasal naloxone appears to be no different than that of naloxone injection in the treatment of opioid overdose in the prehospital setting. CONCLUSION: Intranasal administration of naloxone appears to be effective in treatment of opioid overdose when i.v. administration is impossible or undesirable.

Naloxone for opioid overdose prevention: pharmacists' role in community-based practice settings.

BACKGROUND: Deaths related to opioid overdose have increased in the past decade. Community-based pharmacy practitioners have worked toward overcoming logistic and cultural barriers to make naloxone distribution for overdose prevention a standard and accepted practice. OBJECTIVE: To describe outpatient naloxone dispensing practices, including methods by which practitioners implement dispensing programs, prescribing patterns that include targeted patient populations, barriers to successful implementation, and methods for patient education. METHODS: Interviews were conducted with providers to obtain insight into the practice of dispensing naloxone. Practitioners were based in community pharmacies or clinics in large metropolitan cities across the country. RESULTS: It was found that 33% of participating pharmacists practice in a community-pharmacy setting, and 67% practice within an outpatient clinic-based location. Dispensing naloxone begins by identifying patient groups that would benefit from access to the antidote. These include licit users of high-dose prescription opioids (50%) or injection drug users and abusers of prescription medications (83%). Patients were identified through prescription records or provider screening tools. Dispensing naloxone required a provider's prescription in 5 of the 6 locations identified. Only 1 pharmacy was able to exercise pharmacist prescriptive authority within their practice. CONCLUSION: Outpatient administration of intramuscular and intranasal naloxone represents a means of preventing opioid-related deaths. Pharmacists can play a vital role in contacting providers, provision of products, education of patients and providers, and dissemination of information throughout the community. Preventing opioid overdose-related deaths should become a major focus of the pharmacy profession.

Survey of naloxone legal status in opioid overdose prevention and treatment.

OBJECTIVE: To survey the federal and state-by-state legal status for prescribing, dispensing, and administering naloxone injection. DESIGN: The survey was a review of legislation, which encompassed analyzing current and proposed laws regarding naloxone's role in opioid overdose prevention and treatment. MAIN OUTCOME MEASURE(S): The primary study outcome was to evaluate the legal aspects of current naloxone overdose prevention and treatment. Aspects of the legislation studied included Food and Drug Administration (FDA) regulatory status, prescriber authorization, prescription requirements, defining the patient, authority to administer naloxone, status of lay person administration, and provisions for Good Samaritan protections from criminal and civil liability. RESULTS: To date, 10 states have legislation implementing opioid overdose prevention programs including naloxone. Several states with high opioid overdose burdens are in the legislative process. Reasons for hesitation to initiate such programs include fear of liability, a proxy endorsement for drug abuse, and apprehension of increasing drug usage. CONCLUSIONS: A number of state legislatures have passed legislation permitting lay administration of naloxone to individuals in an attempt to revive a person with an apparent opioid overdose. These emerging state policy initiatives parallel similar laws and regulations governing lay person epinephrine administration for anaphylaxis and applying automated electric defibrillators for sudden cardiac arrest. Public health initiatives increasing access to naloxone will likely continue in states with high opioid overdose burdens. FDA approval of a new needle-free naloxone delivery system would facilitate greater public access.

A response to the opioid overdose epidemic: naloxone nasal spray.

Opioid overdose morbidity and mortality is recognized to have epidemic proportions. Medical and public health agencies are adopting opioid harm reduction strategies to reduce the morbidity and mortality associated with overdose. One strategy developed by emergency medical services and public health agencies is to deliver the opioid antidote naloxone injection intranasally to reverse the effects of opioids. Paramedics have used this route to quickly administer naloxone in a needle-free system and avoiding needle-stick injuries and contracting a blood-born pathogen disease such as hepatitis or human immunodeficiency virus. Public health officials advocate broader lay person access since civilians are likely witnesses or first responders to an opioid overdose in a time-acute setting. The barrier to greater use of naloxone is that a suitable and optimized needlefree drug delivery system is unavailable. The scientific basis for design and study of an intranasal naloxone product is described. Lessons from nasal delivery of opioid analgesics are applied to the consideration of naloxone nasal spray.

Comparison of the behavioral and cardiovascular effects of intranasal and oral d-amphetamine in healthy human subjects.

Recent reports indicate an increase in intranasal use of prescription oral stimulant medication. However, there do not appear to be any published clinical studies that have characterized the behavioral and cardiovascular effects of intranasally administered d-amphetamine, which is commonly prescribed for Attention Deficit Hyperactivity Disorder. In this study, a range of d-amphetamine doses (0, 16, 24, and 32 mg/70 kg) were administered as an intranasal solution delivered using a mucosal atomization device. Equal oral doses were included for comparison. Assessments were conducted before and at regular intervals for 3 hours following drug administration and included self-reported drug-effect questionnaires, cardiovascular indices, a performance task, and 2 measures of impulsivity. d-Amphetamine produced prototypical stimulant effects (eg, increased subject ratings of Stimulated and Like Drug, elevated heart rate and blood pressure, and improved rate and accuracy on the digit symbol substitution task) irrespective of dose, but the onset of these effects was generally earlier following intranasal administration, with significant effects emerging 15 to 30 minutes after intranasal dosing and 45 to 60 minutes after oral dosing. These results demonstrate that intranasal administration of d-amphetamine results in a more rapid onset compared to oral dosing, which could be associated with the popularity of intranasal prescription stimulant use and an enhanced potential for abuse.

A multicenter, open-label, exploratory dose-ranging trial of intranasal hydromorphone for managing acute pain from traumatic injury.

UNLABELLED: We conducted a prospective multicenter, open-label, escalating dose-range trial to compare, across patients, single intranasal doses (2, 4, 6, 8, and 10 mg) of hydromorphone HCl in the treatment of acute trauma pain The main outcome measure of pain-intensity reduction was derived from serial Numerical Pain-Rating Scores and calculated as the summed pain-intensity difference over 3 hours (SPID 3). Nasal examinations, vital signs, and adverse events were reported as safety outcomes. The mean decrease in pain intensity from baseline to 30 minutes was 39 to 44% for the 4-, 6-, 8- and 10-mg doses (n = 19, 33, 28, and 19 per group) and only 24% reduction for the 2-mg dose (n = 14). SPID 3 for the 2-mg dose was 40 to 50% below all other doses. There were no clinically meaningful changes in vital signs or nasal examinations. Adverse events (nausea, vomiting, pruritus, oxygen desaturation, bad taste, dizziness) were of mild to moderate intensity, increased with dose, and expected, based on route of administration and opioid pharmacology. Intranasal hydromorphone provides a component of rapid pain relief in the care of emergency department patients suffering from acute trauma pain. PERSPECTIVE: This article presents a pilot dose-ranging study of intranasally administered hydromorphone, administered in the emergency department to patients suffering from acute trauma pain. This study demonstrates research success in this setting and noninjection-based delivery and certain doses of intranasal hydromorphone may be effective in treating acute trauma pain.

Intranasal delivery of antiepileptic medications for treatment of seizures.

Acute isolated seizure, repetitive or recurrent seizures, and status epilepticus are all deemed medical emergencies. Mortality and worse neurologic outcome are directly associated with the duration of seizure activity. A number of recent reviews have described consensus statements regarding the pharmacologic treatment protocols for seizures when patients are in pre-hospital, institutional, and home-bound settings. Benzodiazepines, such as lorazepam, diazepam, midazolam, and clonazepam are considered to be medications of first choice. The rapidity by which a medication can be delivered to the systemic circulation and then to the brain plays a significant role in reducing the time needed to treat seizures and reduce opportunity for damage to the CNS. Speed of delivery, particularly outside of the hospital, is enhanced when transmucosal routes of delivery are used in place of an intravenous injection. Intranasal transmucosal delivery of benzodiazepines is useful in reducing time to drug administration and cessation of seizures in the pre-hospital setting, when actively seizing patients arrive in the emergency room, and at home where caregivers treat their dependents. This review summarizes factors to consider when choosing a benzodiazepine for intranasal administration, including formulation and device considerations, pharmacology and pharmacokinetic/pharmacodynamic profiles. A review of the most relevant clinical studies in epilepsy patients will provide context for the relative success of this technique with a number of benzodiazepines and relatively less sophisticated nasal preparations. Neuropeptides delivered intranasally, crossing the blood-brain barrier via the olfactory system, may increase the availability of medications for treatment of epilepsy. Consequently, there remains a significant unmet medical need to serve the pharamcotherapeutic requirements of epilepsy patients through commercial development and marketing of intranasal antiepileptic products.

A pharmacokinetic and pharmacodynamic study, in healthy volunteers, of a rapidly absorbed intranasal midazolam formulation.

PURPOSE: To compare 2.5 mg and 5.0 mg single-dose pharmacokinetics (PK), pharmacodynamics (PD) and tolerability of an intranasal (i.n.) midazolam formulation, to a 2.5-mg intravenous (i.v.) dose. METHODS: Design was an open-label, three-way crossover, randomized PK and PD study in seventeen healthy volunteers. Twelve-hour PK parameters were determined for each treatment arm. Subjects completed serial self-ratings for sedation and other drug effects. Nurse observers made serial observations for sedation and adverse effects. An otolaryngologist conducted a nasal endoscopy, pre-dose, 2-4 h, and at end of study, to examine the nasal cavity for formulation-induced changes in nasal anatomy. RESULTS: Midazolam was rapidly absorbed following i.n. administration, with a median t(max) of 10 min; dose proportionate increases for C(max) and AUC; t(1/2) of 4 h; and, 60% (+/-23) nasal administration bioavailability compared to the i.v. dose. PD responses were rapid, paralleled the PK, and in magnitude was in a rank order of i.v. 2.5 mg > or = i.n. 5.0 mg > i.n. 2.5 mg doses. The formulation was well tolerated with no serious cardiovascular or respiratory complications. Fourteen subjects complained of at least one of the following: a brief and mild to moderate intensity facial flushing, nasal passage burning, sore throat or bad taste after drug administration. There were no adverse findings from the nasal endoscopic exam. CONCLUSION: Dosages of an investigational i.n. midazolam formulation resulted in rapid absorption and attained plasma concentrations that correlated with pharmacodynamic effects.

Comparison of intranasal administration of haloperidol with intravenous and intramuscular administration: a pilot pharmacokinetic study.

STUDY OBJECTIVE: To evaluate the pharmacokinetics of haloperidol after intranasal administration compared with intravenous and intramuscular administration, and to evaluate systemic and local tolerance of intranasal administration. DESIGN: Randomized, open-label, three-way crossover study. SETTING: Academic medical center. SUBJECTS: Four healthy volunteers (two men, two women; aged 24-37 yrs). INTERVENTION: Each subject received in a randomized order the following three treatments, with a 2-week washout period between treatments: intravenous haloperidol 2.5 mg (0.5 ml of 5.0 mg/ml) infused over 15 minutes, intramuscular haloperidol 2.5 mg (0.5 ml of 5.0 mg/ml), and intranasal haloperidol 2.5 mg (2.5 mg/0.1-ml spray into a single naris). MEASUREMENTS AND MAIN RESULTS: Blood samples were obtained serially and plasma levels determined. Noncompartmental analysis was used to estimate pharmacokinetic parameters. Physical and nasal examinations and adverse-effect profiles were obtained to assess tolerance. Mean (percent coefficient of variation) haloperidol bioavailability after intranasal administration was 63.8% (24.4%) compared with intravenous administration and 48.6% (29.4%) compared with intramuscular administration. Intranasal administration achieved higher peak levels that occurred more quickly compared with intramuscular administration. Median time to maximum concentration was 15 minutes after the intranasal dose compared with 37.5 and 15 minutes after the intramuscular and intravenous doses, respectively. Subjects had mild-to-moderate systemic adverse effects, all related to an extension of haloperidol's pharmacologic actions. Two of the four subjects complained of mild-tomoderate nasal irritation after the intranasal doses. CONCLUSION: Our results suggest that additional research studies are warranted for further evaluation of intranasal administration of haloperidol. The product provides rapid therapeutic plasma levels and sedation, with only minor and short-lived nasal irritation. These data suggest that intranasal administration of haloperidol, or other antipsychotics with similar potency, could play a role in treating psychiatric emergencies.

Microneedles permit transdermal delivery of a skin-impermeant medication to humans.

Drugs with poor oral bioavailability usually are administered by hypodermic injection, which causes pain, poor patient compliance, the need for trained personnel, and risk of infectious disease transmission. Transdermal (TD) delivery provides an excellent alternative, but the barrier of skin's outer stratum corneum (SC) prevents delivery of most drugs. Micrometer-scale microneedles (MNs) have been used to pierce animal and human cadaver skin and thereby enable TD delivery of small molecules, proteins, DNA, and vaccines for systemic action. Here, we present a clinical study of MN-enhanced delivery of a medication to humans. Naltrexone (NTX) is a potent mu-opioid receptor antagonist used to treat opiate and alcohol dependence. This hydrophilic and skin-impermeant molecule was delivered from a TD patch to healthy human subjects with and without pretreatment of the skin with MNs. Whereas delivery from a standard NTX TD patch over a 72-h period yielded undetectable drug plasma levels, pretreatment of skin with MNs achieved steady-state plasma concentrations within 2 h of patch application and were maintained for at least 48 h. The MNs and NTX patch were well tolerated with mild systemic and application site side effects. The MN arrays were painless upon administration and not damaged during skin insertion, and no MNs were broken off into the skin. This human proof-of-concept study demonstrates systemic administration of a hydrophilic medication by MN-enhanced TD delivery. These findings set the stage for future human studies of skin-impermeant medications and biopharmaceuticals for clinical applications.

Intranasal absorption of Delta(9)-tetrahydrocannabinol and WIN55,212-2 mesylate in rats.

The aim of this study was to examine the potential of the nasal route for systemic delivery of Delta(9)-tetrahydrocannabinol (Delta(9)-THC) and WIN55,212-2 mesylate. Anesthetized rats were surgically prepared to isolate the nasal cavity, into which Delta(9)-THC (10 mg/kg) or WIN55,212-2 (150 microg/kg) in propylene glycol alone or propylene glycol and ethanol (9:1) were administered. Rats were also administered Delta(9)-THC (1 mg/kg) and WIN55,212-2 (150 microg/kg) intravenously in order to determine absolute bioavailabilities of the nasal doses. Plasma Delta(9)-THC and WIN55,212-2 concentrations were determined by liquid chromatography/mass spectroscopy (LC/MS). The pharmacokinetics of the drugs after intranasal administration was best described by a one-compartment model with an absorption phase. WIN55,212-2 was absorbed more rapidly (T(max)=0.2-0.3h) than Delta(9)-THC (T(max)=1.5-1.6h) and to a higher extent than Delta(9)-THC. Addition of ethanol (10%) to the formulations had no significant effect on the C(max) after nasal administration (p>0.05). Furthermore, it had no significant effect on the absolute bioavailability (F(abs)): F(abs)=6.4+/-2.4% and 9.1+/-3.0% for Delta(9)-THC in propylene glycol, with and without ethanol, respectively. For WIN55,212-2, F(abs)=49.9+/-6.9% (propylene glycol alone) and 56.6+/-14.1% (propylene glycol with 10% ethanol). The results of the study showed that systemic delivery of Delta(9)-tetrahydrocannabinol and WIN55,212-2 could be achieved following nasal administration in rats.

Pharmacokinetics and pharmacodynamics of a new intranasal midazolam formulation in healthy volunteers.

We evaluated the pharmacokinetics and pharmacodynamics of single 5-mg doses of midazolam after administration of a novel intranasal (IN) formula, IM, and IV midazolam in an open-label, randomized, 3-way cross-over study in 12 healthy volunteers. IN doses were delivered as 0.1-mL unit-dose sprays of a novel formulation into both naris. Blood samples were taken serially from 0 to 12 h after each dose. Plasma midazolam concentrations were determined by liquid chromatography/mass spectrometry/mass spectrometry. Noncompartmental analysis was used to estimate pharmacokinetic parameters. The mean midazolam bioavailabilities and % coefficient of variation were 72.5 (12) and 93.4 (12) after the IN and IM doses, respectively. Median time to maximum concentration was 10 min for IN doses. Adverse events were minimal with all routes of administration, but nasopharyngeal irritation, eyes watering, and a bad taste were reported after IN doses. Our results support further development of this novel midazolam nasal spray.

Ziconotide infusion for severe chronic pain: case series of patients with neuropathic pain.

Ziconotide intrathecal infusion was recently approved by the United States Food and Drug Administration for the treatment of intractable severe chronic pain. Patients with neuropathic pain make up a significant population among those who experience chronic pain for which there are less than optimal pharmacotherapeutic options. Published clinical trials provide a global view of ziconotide efficacy and safety. A subset of patients in clinical trials obtained complete pain relief, a remarkable finding given the history of drug treatment for neuropathic pain. To provide more information regarding those who respond to ziconotide therapy, we discuss three patients with neuropathic pain who received ziconotide infusion. Two patients with longstanding neuropathic pain, one with complex regional pain syndrome (formerly known as reflex sympathetic dystrophy) of the leg and one with lumbar radiculitis, achieved temporary but complete pain relief from single 5- and 10-microg epidural test doses. In the third case, a patient with longstanding bilateral leg and foot neuropathic pain from acquired immunodeficiency syndrome and antiretroviral drug therapy achieved considerable pain relief from a long-term continuous intrathecal infusion. The patients who received a single dose had mild central nervous system adverse effects such as sedation, somnolence, nausea, headache, and lightheadedness. The patient who received the intrathecal infusion experienced mild-to-severe adverse effects depending on the rate of infusion; these effects included sedation, confusion, memory impairment, slurred speech, and double vision. This patient could sense impending adverse effects and made rate adjustments or suspended infusion to avert untoward symptoms. In all three cases, patients achieved considerable pain relief that was long-lasting and persisted well after dose administration or suspension of infusion.

Ziconotide, an intrathecally administered N-type calcium channel antagonist for the treatment of chronic pain.

Ziconotide is a novel peptide that blocks the entry of calcium into neuronal N-type voltage-sensitive calcium channels, preventing the conduction of nerve signals. N-type calcium channels are present in the superficial laminae of the dorsal horn of the spinal cord. In various animal models of pain, intrathecal administration of ziconotide blocked nerve transmission and nociception. The United States Food and Drug Administration recently approved ziconotide intrathecal infusion for the management of severe chronic pain in patients who require intrathecal therapy and who are intolerant of or refractory to other treatment, such as systemic analgesics, adjunctive therapies, or intrathecal morphine. The drug has a narrow therapeutic window and a lag time for the onset and offset of analgesia and adverse events. In early clinical trials, frequent and severe psychiatric and central nervous system adverse effects were associated with rapid intrathecal infusion (0.4 microg/hr) and frequent up-titration (every 12 hrs). Therefore, patients with psychiatric symptoms are not candidates for this drug. Drug trials of external intrathecal catheters and microinfusion devices demonstrated a 3% risk of meningitis. A low initial infusion rate of 0.1 microg/hour and limiting infusion rate increases to 2-3 times/week are now recommended. Patients responsive to intrathecal ziconotide require an implanted infusion system to receive long-term therapy.

Analgesic effects of intranasal butorphanol tartrate administered via a unit-dose device in the dental impaction pain model: a randomized, double-blind, placebo-controlled, parallel-group study.

BACKGROUND: Butorphanol tartrate (BT) nasal spray is currently marketed as a multidose spray pump product. However, access to excessive amounts of drug in a single bottle (up to 15 doses) creates the potential for misuse, diversion, and abuse. OBJECTIVE: This study evaluated the efficacy and tolerability of a sterile, unpreserved BT nasal spray administered via a unit-dose device in the treatment of moderate to severe pain after dental impaction surgery. METHODS: This was a single-site, single-dose, randomized, double-blind, placebo-controlled, parallel-group pilot study of unit-dose BT nasal spray 1 and 2 mg compared with vehicle in patients who received standard anesthesia and underwent surgery to remove impacted third molars. When patients reported experiencing moderate or severe postoperative pain, they were assigned to receive the respective treatments in a 2:2:1 ratio. Patients rated pain intensity and pain relief and performed other assessments of analgesic efficacy before dosing and at 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 3, 4, and 6 hours after receipt of study medication. They could request rescue medication from 1 hour after the administration of nasal spray. The primary efficacy variables were summed pain intensity difference (SPID) at 2, 4, and 6 hours after administration of study medication and total pain relief at 6 hours (TOTPAR-6). Vital signs, pulse oximetry, and adverse events were monitored on the same schedule as pain assessments. RESULTS: Thirty men and 30 women were enrolled (mean [SD] age, 22.5 [3.8] years; mean body weight, 168 [41.3] lb) and completed the trial. Pain relief was recorded in most patients within 15 minutes of receiving active treatment. A dose response was observed in SPID scores, with the 2-mg dose of BT providing the greatest response compared with placebo (P < 0.05). Overall, 52 (86.7%) patients requested rescue medication: 22 of 24 (91.7%) in the 1-mg group, 19 of 24 (79.2%) in the 2-mg group, and 11 of 12 (91.7%) in the placebo group. The time to use of rescue medication occurred a median of 75 to 110 minutes after nasal spray dosing. The analysis of TOTPAR-6 showed no significant differences overall or in pairwise comparisons. On the global assessment, 58.3% of patients in each of the active-treatment groups and 83.3% of patients in the placebo group evaluated the study drug as "poor." The unit-dose BT nasal spray was well tolerated, with central nervous system adverse effects being most common in the active-treatment groups compared with placebo (P = 0.029). Dizziness occurred in 11 (45.8%) patients who received BT 1 mg, 14 (58.3%) who received BT 2 mg, and 4 (33.3%) who received placebo; for headache, the corresponding numbers were 11 (45.8%), 7 (29.2%), and 2 (16.7%). There were no significant changes from baseline in vital signs, pulse oximetry, reported nasal irritation, or pathology (eg, irritation, epistaxis, ulceration). CONCLUSIONS: In this small pilot study, sterile BT nasal spray administered via a unit-dose device provided effective postsurgical analgesia in approximately half of patients who had undergone surgery to remove impacted third molars. The results are similar to those of previous studies of BT nasal spray administered via multidose pump for postsurgical analgesia in the dental impaction pain model. The outcomes of this study are limited to the population studied.

Bioavailability of intranasal butorphanol administered from a single-dose sprayer.

PURPOSE: The bioavailability and tolerability of single doses of intranasal butorphanol tartrate using a single-dose, metered sprayer were studied. METHODS: In this open-label, randomized, three-way crossover study, 24 healthy volunteers received three treatments: (1) 2 mg of i.v. butorphanol (treatment A), (2) 2 mg of intranasal butorphanol (treatment B), and (3) 1 mg of intranasal butorphanol (treatment C). The three treatments received by each subject were separated by six-day washout periods. Venous blood samples (10 mL each) were obtained from an indwelling catheter at 0 (predose), 5, 10, 15,20,30, and 45 minutes and 1,2,3,4,6,8, 12, and 16 hours after butorphanol administration. Pharmacokinetic parameters were determined using standard noncompartmental methods with log-linear least-squares regression analysis to determine the elimination-rate constants. RESULTS: Intranasal butorphanol 1 and 2 mg administered using unit dose sprayers had a mean bioavailability of approximately 80%, which is higher than the percentage reported with the commercially available multidose product (61-69%). The absorption of intranasal butorphanol was rapid, with a median time to reach maximum concentration of 20 minutes (range, 10-60 minutes). Elimination profiles were comparable among all treatments. There were no clinically significant changes in the results of physical examinations, nasal evaluations, or laboratory tests related to butorphanol treatment. Most adverse effects reported were mild to moderate and as expected for this drug. CONCLUSION: Single-dose intranasal butorphanol was rapidly absorbed and had high absolute bioavailability in healthy volunteers.

Intranasal delivery of recombinant human parathyroid hormone [hPTH (1-34)], teriparatide in rats.

The aim of this study was to explore the nasal route as an alternative to daily subcutaneous injections of hPTH (1-34). Anesthetized rats were surgically prepared and nasally dosed with aqueous solutions of hPTH (1-34). Plasma samples were assayed by radioimmunoassay and data generated fit to two-(intravenous) and one-(intranasal) compartment pharmacokinetic models using WinNonlin. The toxicity of hPTH (1-34) solution administered to the rats was assessed by screening its effect on transepithelial electrical resistance, potential difference, paracellular marker permeation, tissue viability, and protein leakage using the EpiAirway tissue model. The intranasal absorption of hPTH (1-34) was rapid; the absorption rate constants (alpha) were 33.2+/-24 h(-1) [without bovine serum albumin (BSA)] and 9.8+/-5.1 h(-1) (with 1% BSA). The maximum plasma concentrations (Cmax): 151+/-24 pg/mL (without BSA) and 176+/-37 (with 1% BSA) were attained within approximately 15 min. The intranasal bioavailabilities (Fabs) were 12.1+/-3.4% (without BSA) and 17.6+/-1.5% (with 1% BSA). The hPTH (1-34) formulation administered to the rats had no detrimental effect on the EpiAirway tissue epithelial electrical parameters and functional integrity. Based on the results of this study, the nasal route appears to be a prospective alternative to subcutaneous injections of hPTH (1-34).