Seizing child recieving IN treatmentTherapeutic Intranasal Drug Delivery

Needleless treatment options for medical problems

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Miscellaneous medications for use as intranasal therapy - abstracted references:

Andrade, C. (2015). "Intranasal drug delivery in neuropsychiatry: focus on intranasal ketamine for refractory depression." J Clin Psychiatry 76(5): 628-631.

Intranasal drug delivery (INDD) systems offer a route to the brain that bypasses problems related to gastrointestinal absorption, first-pass metabolism, and the blood-brain barrier; onset of therapeutic action is rapid, and the inconvenience and discomfort of parenteral administration are avoided. INDD has found several applications in neuropsychiatry, such as to treat migraine, acute and chronic pain, Parkinson disease, disorders of cognition, autism, schizophrenia, social phobia, and depression. INDD has also been used to test experimental drugs, such as peptides, for neuropsychiatric indications; these drugs cannot easily be administered by other routes. This article examines the advantages and applications of INDD in neuropsychiatry; provides examples of test, experimental, and approved INDD treatments; and focuses especially on the potential of intranasal ketamine for the acute and maintenance therapy of refractory depression.

 

Bell, Rf, et al. (2004). "Is intranasal ketamine an appropriate treatment for chronic non-cancer breakthrough pain?" Pain 108(1-2): 1-2.

Buckley, R., T. McCurry, et al. (2000). "Intranasal lidocaine for migraine using a metered-dose spray." Headache 40(6): 498.

Carr, D. B., L. C. Goudas, et al. (2004). "Safety and efficacy of intranasal ketamine for the treatment of breakthrough pain in patients with chronic pain: a randomized, double-blind, placebo-controlled, crossover study." Pain 108(1-2): 17-27.

            Few placebo-controlled trials have investigated the treatment of breakthrough pain (BTP) in patients with chronic pain. We evaluated the efficacy and safety of intranasal ketamine for BTP in a randomized, double-blind, placebo-controlled, crossover trial. Twenty patients with chronic pain and at least two spontaneous BTP episodes daily self-administered up to five doses of intranasal ketamine or placebo at the onset of a spontaneous BTP episode (pain intensity > or =5 on a 0-10 scale). Two BTP episodes at least 48 h apart were treated with either ketamine or placebo. Patients reported significantly lower BTP intensity following intranasal ketamine than after placebo (P < 0.0001) with pain relief within 10 min of dosing and lasting for up to 60 min. No patient in the ketamine group required his/her usual rescue medication to treat the BTP episode, while seven out of 20 (35%) patients in placebo group did (P = 0.0135). Intranasal ketamine was well tolerated with no serious adverse events. After ketamine administration, four patients reported a transient change in taste, one patient reported rhinorrhea, one patient reported nasal passage irritation, and two patients experienced transient elevation in blood pressure. A side effect questionnaire administered 60 min and 24 h after drug or placebo administration elicited no reports of auditory or visual hallucinations. These data suggest that intranasal administration of ketamine provides rapid, safe and effective relief for BTP.

Cho, E., H. Gwak, et al. (2008). "Formulation and evaluation of ondansetron nasal delivery systems." Int J Pharm 349(1-2): 101-7.

            This study aimed to formulate and evaluate nasal delivery systems containing ondansetron hydrochloride. In the in vitro study, the permeation rate with the addition of 10% polyethylene glycol 300 (PEG 300) to aqueous solution containing 0.01% benzalkonium chloride (BC) and 10% sulfobutylether beta-cyclodextrin sodium salt (SBCD) was somewhat more rapid up to 1.5h compared to the addition of 10% PG. The permeation flux increased as the drug concentration increased regardless of the vehicles used. The addition of nicotinamide or chitosan to aqueous drug solution (40 mg/ml) with 10% PEG 300 and 0.01% BC rather decreased permeation rate and delayed lag time. Even though cyclodextrins including SBCD or dimethyl-ss-cyclodextrin failed to show permeation enhancing effects of ondansetron hydrochloride, the addition of 10% SBCD to aqueous solution containing 10% PEG 300 and 0.01% BC could be a good candidate for ondansetron nasal delivery systems because of its safety profile, stable storage in refrigerator and solubilizing effect. With the above formulation, the nasal delivery system increased AUC0-2h and Cmax by 2.1 and 1.7 times compared to those of oral delivery, respectively while there was no difference found in AUC0-2h with intravenous administration. Therefore, the nasal delivery system of ondansetron hydrochloride formulated in this study was feasible for nasal administration.

Claxton, A., L. D. Baker, et al. (2014). "Long-Acting Intranasal Insulin Detemir Improves Cognition for Adults with Mild Cognitive Impairment or Early-Stage Alzheimer's Disease Dementia." J Alzheimers Dis.

Previous trials have shown promising effects of intranasally administered insulin for adults with Alzheimer's disease dementia (AD) or amnestic mild cognitive impairment (MCI). These trials used regular insulin, which has a shorter half-life compared to long-lasting insulin analogues such as insulin detemir. The current trial examined whether intranasal insulin detemir improves cognition or daily functioning for adults with MCI or AD. Sixty adults diagnosed with MCI or mild to moderate AD received placebo (n = 20), 20 IU of insulin detemir (n = 21), or 40 IU of insulin detemir (n = 19) for 21 days, administered with a nasal drug delivery device. Results revealed a treatment effect for the memory composite for the 40 IU group compared with placebo (p < 0.05). This effect was moderated by APOE status (p < 0.05), reflecting improvement for APOE-epsilon4 carriers (p < 0.02), and worsening for non-carriers (p < 0.02). Higher insulin resistance at baseline predicted greater improvement with the 40 IU dose (r = 0.54, p < 0.02). Significant treatment effects were also apparent for verbal working memory (p < 0.03) and visuospatial working memory (p < 0.04), reflecting improvement for subjects who received the high dose of intranasal insulin detemir. No significant differences were found for daily functioning or executive functioning. In conclusion, daily treatment with 40 IU insulin detemir modulated cognition for adults with AD or MCI, with APOE-related differences in treatment response for the primary memory composite. Future research is needed to examine the mechanistic basis of APOE-related treatment differences, and to further assess the efficacy and safety of insulin detemir.

Cleary, J. F. (1997). "Pharmacokinetic and pharmacodynamic issues in the treatment of breakthrough pain." Semin Oncol 24(5 Suppl 16): S16-13-9.

Costa, A., E. Pucci, et al. (2000). "The effect of intranasal cocaine and lidocaine on nitroglycerin-induced attacks in cluster headache." Cephalalgia 20(2): 85-91.

            The administration of nitroderivatives in cluster headache (CH) sufferers is the most reproducible experimental paradigm to induce spontaneous-like pain attacks. Previous uncontrolled studies have reported that the local use of anaesthetic agents in the area of the sphenopalatine fossa is able to extinguish nitroglycerin (NTG)-induced pain in CH. The present study, carried out according to a double-blind placebo-controlled design, included 15 CH patients, six with episodic CH (mean +/- SD age of 36.8+/-5.6 years), and nine with chronic CH (37.8+/-10.4 years). Patients had undergone a standard NTG test (0.9 mg sublingually), during which the intensity of pain was scored using a visuoanalogic scale (VAS, range 0-10). Nine patients (two with the episodic form, seven with the chronic form) experienced a typical, spontaneous-like attack on the usual side, occurring in all cases within 45 min. In these patients, the test was repeated with an interval of 2 days, and once pain intensity reached 5 on the VAS, a 10% solution of cocaine hydrochloride (1 ml, mean amount per application 40-50 mg), or 10% lidocaine (1 ml), or saline was applied using a cotton swab in the area corresponding to the sphenopalatine fossa, under anterior rhinoscopy. This was done in both the symptomatic and the non-symptomatic side, for 5 min. Treatments were always performed randomly, in separate sessions. All patients responded promptly to both anaesthetic agents, with complete cessation of induced pain occurring after 31.3+/-13.1 min for cocaine and 37.0+/-7.8 min for lidocaine (M+/-SD). In the case of saline application, pain severity increased thereafter, and extinction of the provoked attacks occurred with a latency of 59.3+/-12.3 min (P&lt;0.01 and P&lt;0.01 vs. cocaine and lidocaine, respectively, Mann-Whitney U-test). While further suggesting that the sphenopalatine ganglion participates in the mechanisms of pain, these findings indicate that the local administration of the anaesthetic agents cocaine and lidocaine is effective on NTG-induced CH attacks, and may be used in the symptomatic treatment of this disorder.

Dash, S., C. Xiao, et al. (2014). "Intranasal insulin suppresses endogenous glucose production in humans compared to placebo, in the presence of similar venous insulin concentration." Diabetes.

Intranasal insulin (INI) has been shown to modulate food intake and food related activity in the central nervous system in humans. As INI increases cerebrospinal fluid insulin concentration, these effects have been postulated to be mediated via insulin action in the brain, although peripheral effects of insulin cannot be excluded. INI has been shown to lower plasma glucose in some studies but it is not known whether it regulates endogenous glucose production (EGP).To assess the role of INI in the regulation of EGP, 8 healthy men were studied in a single-blind, crossover study with 2 randomized visits (one with 40 IU INI and the other with intranasal placebo (INP) administration) 4 weeks apart. EGP was assessed under conditions of an arterial pancreatic clamp, with a primed, constant infusion of deuterated glucose and infusion of 20% dextrose as required to maintain euglycemia.Between 180 and 360 minutes after administration, INI significantly suppressed EGP by 35.6% compared to INP, despite similar venous insulin concentrations.In conclusion, INI lowers EGP in humans compared to INP, despite similar venous insulin, under experimental conditions of relative portal hypoinsulinemia. INI may therefore be of value in treating excess liver glucose production in diabetes.

Dean, H. J. (2006). "Alternative routes of influenza vaccine delivery." Expert Opin Drug Deliv 3(5): 557-61.

            The global emergence of virulent avian influenza and the concomitant raised threat of an influenza pandemic has increased interest in the development of improved influenza vaccines. Whereas conventional influenza vaccines are delivered by parenteral injection, an intranasal influenza vaccine has been marketed since 2003. Many other technologies are in development for intranasal, oral, epidermal and topical influenza vaccines. This editorial summarises the advances in clinical development of technologies for needle-free influenza vaccine delivery.

Eyles, J. E., E. D. Williamson, et al. (2000). "Intranasal Administration of InfluenzaVaccines: Current Status." BioDrugs 13(1): 35-59.

            Abstract This review article focuses on intranasal immunisation against influenza, although it also encompasses antigen uptake and processing in the nasopharyngeal passages, host defense from influenza and current influenza vaccination practices. Improvement of current vaccination strategies is clearly required; current procedures involve repeated annual injections that sometimes fail to protect the recipient. It is envisaged that nonpercutaneous immunisation would be more attractive to potential vaccinees, thus improving uptake and coverage. As well as satisfying noninvasive criteria, intranasal influenza immunisation has a number of perceived immunological advantages over current procedures. Perhaps one of the greatest attributes of this approach is its potential to evoke the secretion of haemagglutinin-specific IgA antibodies in the upper respiratory tract, the main site of viral infection. Inactivated influenza vaccines have the advantage that they have a long history of good tolerability as injected immunogens, and in this respect are possibly more likely to be licensed than attenuated viruses. Inert influenza vaccines are poor mucosal immunogens, requiring several administrations, or prior immunological priming, in order to engender significant antibody responses. The use of vaccine delivery systems or mucosal adjuvants serves to appreciably improve the immunogenicity of mucosally applied inactivated influenza vaccines. As is the case when they are introduced parenterally, inactivated influenza vaccines are relatively poor stimulators of virus-specific cytotoxic T lymphocyte activity following nasal inoculation. Live attenuated intranasal influenza vaccines are at a far more advanced stage of clinical readiness (phase III versus phase I). With the use of live attenuated vaccines, it is possible to stimulate mucosal and cell-mediated immunological responses of a similar kind to those elicited by natural influenza infection. In children, recombinant live attenuated cold-adapted influenza viruses are well tolerated. Moreover, cold-adapted influenza viruses usually stimulate protective immunity following only a single nasal inoculation. Safety of recombinant live attenuated cold-adapted influenza viruses has also been demonstrated in high risk individuals with cystic fibrosis, asthma, cardiovascular disease and diabetes mellitus. They are not suitable for immunising immunocompromised patients, however, and are poorly efficacious in individuals with pre-existing immunity to strains closely antigenically matched with the recombinant virus. According to the reviewed literature, it is apparent that intranasal administration of vaccine as an aerosol is superior to administration as nose drops. The information reviewed in this paper suggests that nasally administered influenza vaccines could make a substantial impact on the human and economic cost of influenza.

Flood, P. and D. Daniel (2004). "Intranasal nicotine for postoperative pain treatment." Anesthesiology 101(6): 1417-21.

            BACKGROUND: Despite pharmacological treatment, 70-80% of patients report moderate to severe pain after surgery. Because nicotine has been reported to have analgesic properties in animal and human volunteer studies, the authors assessed the analgesic efficacy of a single 3 mg dose of nicotine nasal spray administered before emergence from general anesthesia. METHODS: The authors conducted a randomized, double blind, placebo controlled trial of 20 healthy women (mean age 45 (SD 8) yr) who were to undergo uterine surgery through a low transverse incision. After the conclusion of surgery but before emergence from general anesthesia, the anesthesiologist administered either nicotine nasal spray or a placebo. Numerical analog pain score and morphine utilization and hemodynamic values were measured for 24 h. RESULTS: The patients treated with nicotine reported lower pain scores during the first hour after surgery (peak numerical analog score, 7.6 (SD 1.4) versus 5.3 (SD 1.6); P < 0.001) and used half the amount of morphine as the control group (12 (SD 6) versus 6 (SD 5) mg; P < 0.05). Patients who received nicotine still reported less pain than those in the control group 24 h after surgery (1.5 (SD 0.5) versus 4.9 (SD 1.4); P < 0.01). Systolic blood pressure was lower in the group that received nicotine (105 (SD 3) versus 122 (SD 3); P < 0.001), but there was no difference in diastolic blood pressure or heart rate. CONCLUSIONS: Treatment with a single dose of nicotine immediately before emergence from anesthesia was associated with significantly lower reported pain scores during the first day after surgery. The decreased pain was associated with a reduction in morphine utilization and the analgesic effect of nicotine was not associated with hypertension or tachycardia.

Giraud, P, et al. "Cluster Headache During Pregnancy: Case Report and Literature Review." Headache Jan 2009: 136-139

A 32-year-old pregnant woman presented with cluster headache (CH) during the third trimester of a normal pregnancy. Pure oxygen mask inhalation was ineffective, and intranasal lidocaine applications were realized associated with oral methylprednisolone, given at 1 mg per kg once daily. These treatments rendered the pain tolerable and the pregnancy went to its term with no consequence on the baby. This case of CH attack during pregnancy raises the issues of the influence of sexual hormonal changes in women with CH and the way to treat this disease in such circumstance. To date, there are no therapeutic guidelines available; this case suggests some possibilities.

Goudas, L. C., D. B. Carr, et al. (2002). "Efficacy and safety of intranasal ketamine for the management of breakthrough pain in chronic pain. A randomized, double-blind, placebo-controlled, cross-over trial." American Society of Clinical Oncology Meeting Abstract No:             450.

            Breakthrough Pain (BTP) is common (prevalence: 19% to 93%) among chronic pain patients, however few placebo-controlled trials have investigated BTP in these patients. Breakthrough pain management typically involves dosage increases of round-the-clock opioids and/or supplemental rescue doses of short-acting opioids or fixed-dose mixtures with NSAIDs. These medications have a relatively slow onset of action, rendering them inadequate in treating severe, paroxysmal BTP. The large surface area and local vascularity of the nasal mucosa offers an ideal route for rapid delivery of drugs into the systemic circulation. To evaluate the efficacy and safety of intranasal ketamine HCl, we performed a randomized, double-blind, placebo-controlled, cross-over trial in 20 patients suffering from chronic pain. Patients experiencing at least 2 BTP episodes daily were randomized to receive ketamine and placebo intranasally. Patients self-administered up to 5 fixed doses (10 mg each, up to 50 mg per episode) of drug or placebo at the onset of BTP (intensity of BTP > 5 on a 0 to 10 numeric scale). Two BTP episodes, each on a separate day, were treated with either ketamine or placebo. Patients reported significantly lower intensity of their BTP episode following intranasal ketamine as compared to placebo (p<0.0001). Onset of pain relief occurred within 5 minutes of dosing with ketamine and lasted up to 60 minutes. No patient in the ketamine group required his/her regular rescue medication, while 7/20 (35%) in the placebo group did (p=0.0135). Intranasal ketamine was well-tolerated with no serious adverse events reported. In the ketamine group, there were 4 reports of change in taste (20%), and one report each of rhinorrhea (5%), throat irritation (5%), and nasal irritation (5%). Some patients (20%) reported varying degrees of dizziness and a feeling of unreality, resolving within 60 minutes. No patients reported hallucinations. These data suggest that intranasal ketamine provides rapid, safe, and effective relief for breakthrough pain that may reduce the need for short-acting opioids.

Guastella, A. J., K. M. Gray, et al. (2014). "The effects of a course of intranasal oxytocin on social behaviors in youth diagnosed with autism spectrum disorders: a randomized controlled trial." J Child Psychol Psychiatry.

BACKGROUND: There is increasing interest in oxytocin as a therapeutic to treat social deficits in autism spectrum disorders (ASD). The aim of this study was to investigate the efficacy of a course of oxytocin nasal spray to improve social behavior in youth with ASD. METHODS: In a double-blind, placebo-controlled trial across two Australian university sites between February 2009 and January 2012, 50 male participants aged between 12 and 18 years, with Autistic or Asperger's Disorder, were randomized to receive either oxytocin (n = 26) or placebo (n = 24) nasal sprays (either 18 or 24 International Units), administered twice-daily for 8 weeks. Participants were assessed at baseline, after 4- and 8-weeks of treatment, and at 3-month follow-up. Primary outcomes were change in total scores on the caregiver-completed Social Responsiveness Scale and clinician-ratings on the Clinical Global Impressions-Improvement scale. Secondary assessments included caregiver reports of repetitive and other developmental behaviors and social cognition. Clinical trial registration: Australian New Zealand Clinical Trials Registry www.anzctr.org.au ACTRN12609000513213. RESULTS: Participants who received oxytocin showed no benefit following treatment on primary or secondary outcomes. However, caregivers who believed their children received oxytocin reported greater improvements compared to caregivers who believed their child received placebo. Nasal sprays were well tolerated and there was no evidence of increased side effects resulting from oxytocin administration. CONCLUSIONS: This is the first evaluation of the efficacy for a course of oxytocin treatment for youth with ASD. Although results did not suggest clinical efficacy, further research is needed to explore alternative delivery methods, earlier age of intervention, and the influence of caregiver expectation on treatment response.

Kim, Y. R., C. H. Kim, et al. (2014). "The impact of intranasal oxytocin on attention to social emotional stimuli in patients with anorexia nervosa: a double blind within-subject cross-over experiment." PLoS One 9(6): e90721.

BACKGROUND AND AIM: Social factors may be of importance causally and act as maintenance factors in patients with anorexia nervosa. Oxytocin is a neuromodulatory hormone involved in social emotional processing associated with attentional processes. This study aimed to examine the impact of oxytocin on attentional processes to social faces representing anger, disgust, and happiness in patients with anorexia nervosa. METHOD: A double-blind, placebo-controlled within-subject crossover design was used. Intranasal oxytocin or placebo followed by a visual probe detection task with faces depicting anger, disgust, and happiness was administered to 64 female subjects: 31 patients with anorexia nervosa and 33 control students. RESULTS: Attentional bias to the disgust stimuli was observed in both groups under the placebo condition. The attentional bias to disgust was reduced under the oxytocin condition (a moderate effect in the patient group). Avoidance of angry faces was observed in the patient group under the placebo condition and vigilance was observed in the healthy comparison group; both of these information processing responses were moderated by oxytocin producing an increase in vigilance in the patients. Happy/smiling faces did not elicit an attentional response in controls or the patients under either the placebo or oxytocin conditions. CONCLUSION: Oxytocin attenuated attentional vigilance to disgust in patients with anorexia nervosa and healthy controls. On the other hand, oxytocin changed the response to angry faces from avoidance to vigilance in patients but reduced vigilance to anger in healthy controls. We conclude that patients with anorexia nervosa appear to use different strategies/circuits to emotionally process anger from their healthy counterparts.

Koch, S. B., M. van Zuiden, et al. (2014). "Intranasal oxytocin as strategy for medication-enhanced psychotherapy of PTSD: salience processing and fear inhibition processes." Psychoneuroendocrinology 40: 242-256.

About ten percent of people experiencing a traumatic event will subsequently develop post-traumatic stress disorder (PTSD). PTSD is characterized by an exaggerated fear response which fails to extinguish over time and cannot be inhibited in safe contexts. The neurobiological correlates of PTSD involve enhanced salience processing (i.e. amygdala, dorsal anterior cingulate cortex (dACC) and anterior insula (AI) hyperactivity), and reduced top-down inhibitory control over this fear response (i.e. dorsal and ventromedial prefrontal cortex (vmPFC) hypoactivity and diminished structural and functional connectivity between the vmPFC, hippocampus and amygdala). Therefore, dampening the exaggerated fear response (i.e. by reducing amygdala hyperactivity) and enhancing top-down inhibitory control (i.e. by promoting prefrontal control over the amygdala) during psychotherapy is an important target for medication-enhanced psychotherapy (MEP) in PTSD patients. Since the neuropeptide oxytocin (OT) has been found to act on these two processes, we propose that OT is a promising pharmacological agent to boost treatment response in PTSD. Human fMRI studies indicate that intranasal OT attenuates amygdala (hyper)activity and enhances connectivity of the amygdala with the vmPFC and hippocampus, resulting in increased top-down control over the fear response. In addition, intranasal OT was found to attenuate amygdala-brainstem connectivity and to change activity and connectivity in nodes of the salience network (i.e. AI and dACC). Furthermore, OT administration may modulate hypothalamus-pituitary-adrenal (HPA) axis and autonomic nervous system (ANS) function and may enhance social behaviour, which could be beneficial in the therapeutic alliance. We also discuss contextual and interindividual factors (e.g. gender and social context) which may influence the effectiveness of OT in MEP. In all, we propose that intranasal OT given prior to each psychotherapy session may be an effective additive treatment to boost treatment response in PTSD.

Kudrow, L., D. B. Kudrow, et al. (1995). "Rapid and sustained relief of migraine attacks with intranasal lidocaine: preliminary findings." Headache 35(2): 79-82.

            In a noncontrolled study, 23 migraine headache patients were treated with intranasal instillation of 0.4 mL of a 4% lidocaine solution during attacks of varying intensities. Evaluated were pretreatment and posttreatment changes in pain intensity, nausea, and side effects. Posttreatment intensity ratings significantly improved over pretreatment ratings, as determined by a Sandler A analysis (0.077; P < .0005). Migraine attacks were aborted in 12 of 23 patients, of which 8 were completely relieved within 5 minutes. In no case did an aborted attack return to more than a dull level within 24 hours, as determined by follow-up telephone calls. A successful response of migraine attacks to lidocaine treatment was more apt to occur in patients having migraine solely, when compared to migraine patients who also had daily dull headaches; the difference was not significant. Unilateral attacks, however, were significantly more treatment-responsive when compared to bilateral attacks (X2 = 3.85; P = .05). Nausea, associated with migraine attacks in 6 of 12 responders, was similarly aborted by lidocaine in 5 of 6 patients. Other side effects included mild nasal and eye burning of short duration (seconds), and oropharyngeal numbness of approximately 20 minutes' duration. Despite the abrupt and absolute relief of migraine attacks afforded by lidocaine in most of our study patients, its level of efficacy awaits results of double-blind, placebo-controlled studies. Our findings raise new questions regarding the differential pathogenesis of migraine and cluster headache attacks.(ABSTRACT TRUNCATED AT 250 WORDS)

Lapidus, K. A., C. F. Levitch, et al. (2014). "A Randomized Controlled Trial of Intranasal Ketamine in Major Depressive Disorder." Biol Psychiatry.

BACKGROUND: The N-methyl-D-aspartate glutamate receptor antagonist ketamine, delivered via an intravenous route, has shown rapid antidepressant effects in patients with treatment-resistant depression. The current study was designed to test the safety, tolerability, and efficacy of intranasal ketamine in patients with depression who had failed at least one prior antidepressant trial. METHODS: In a randomized, double-blind, crossover study, 20 patients with major depression were randomly assigned, and 18 completed 2 treatment days with intranasal ketamine hydrochloride (50 mg) or saline solution. The primary efficacy outcome measure was change in depression severity 24 hours after ketamine or placebo, measured using the Montgomery-Asberg Depression Rating Scale. Secondary outcomes included persistence of benefit, changes in self-reports of depression, changes in anxiety, and proportion of responders. Potential psychotomimetic, dissociative, hemodynamic, and general adverse effects associated with ketamine were also measured. RESULTS: Patients showed significant improvement in depressive symptoms at 24 hours after ketamine compared to placebo (t = 4.39, p < .001; estimated mean Montgomery-Asberg Depression Rating Scale score difference of 7.6 +/- 3.7; 95% confidence interval, 3.9-11.3). Response criteria were met by 8 of 18 patients (44%) 24 hours after ketamine administration compared with 1 of 18 (6%) after placebo (p = .033). Intranasal ketamine was well tolerated with minimal psychotomimetic or dissociative effects and was not associated with clinically significant changes in hemodynamic parameters. CONCLUSIONS: This study provides the first controlled evidence for the rapid antidepressant effects of intranasal ketamine. Treatment was associated with minimal adverse effects. If replicated, these findings may lead to novel approaches to the pharmacologic treatment of patients with major depression.

Lassmann-Vague, V. and D. Raccah (2006). "Alternatives routes of insulin delivery." Diabetes Metab 32(5 Pt 2): 513-22.

            Optimal glycaemic control is necessary to prevent diabetes-related complications. An intensive treatment, which could mimic physiological insulin secretion, would be the best one. However subcutaneous insulin treatment is not physiologic and represents a heavy burden for patients with type 1 and type 2 diabetes mellitus. Consequently, more acceptable, at least as effective, alternative routes of insulin delivery have been developed over the past years. Up to now, only pulmonary administration of insulin (inhaled insulin) has become a feasible alternative to cover mealtime insulin requirements and one of the various administration systems was recently approved for clinical use in Europe and the United States. But, due to advances in technology, other routes, such as transdermal or oral (buccal and intestinal) insulin administration, could become feasible in a near future, and they could be combined together to offer non-invasive, efficacious and more physiological way of insulin administration to patients with diabetes.

Lin, K. (2007). "Intranasal influenza vaccine may be a safe, effective option for many children." J Pediatr 151(1): 102-3.

Logemann, C. D. and L. M. Rankin (2000). "Newer intranasal migraine medications." Am Fam Physician 61(1): 180-6.

            Two new intranasal migraine medications, sumatriptan and dihydroergotamine mesylate, may offer specific advantages for patients who are seeking alternatives to various oral or parenteral migraine abortive therapies. Placebo-controlled clinical studies demonstrate that both intranasal forms are effective in relieving migraine headache pain, but published clinical trial information comparing these two intranasal medications with current abortive therapies is lacking. Both agents are generally well tolerated by patients, with the exception of mild, local adverse reactions of the nose and throat.

Maizels, M. and A. M. Geiger (1999). "Intranasal lidocaine for migraine: a randomized trial and open-label follow-up." Headache 39(8): 543-51.

            OBJECTIVE: To study the efficacy of intranasal lidocaine for the treatment of migraine when administered by subjects in a nonclinic setting. DESIGN: A 1-month, randomized, controlled, double-blind trial, followed by a 6-month open-label follow-up. SETTING: Ambulatory subjects treating themselves outside of a medical setting. SUBJECTS: One hundred thirty-one adult subjects with migraine, diagnosed according to International Headache Society criteria, were enrolled in the study: 113 treated at least one headache in the controlled trial, and 74 treated at least one headache in the open-label phase. All subjects were members of the Kaiser Permanente Southern California Medical Care Program and were recruited at two urban medical centers. INTERVENTION: Intranasal lidocaine 4% or saline placebo 0.5 mL was dropped into the nostril on the side of the headache, or bilaterally for bilateral headache, according to study protocol. MAIN OUTCOME MEASURES: Trial: percent of headaches relieved to mild or none at 15 minutes and relapse of headache within 24 hours. Open-label: percent of headaches relieved to mild or none at 15 and 30 minutes and relapse within 24 hours. RESULTS: In the controlled trial, headache was relieved within 15 minutes in 34 (35.8%) of 95 subjects treated with 4% intranasal lidocaine compared with 8 (7.4%) of 108 subjects receiving placebo (P &lt; .001). Headaches relapsed in 7 (20.6%) of 34 subjects treated with 4% intranasal lidocaine compared to 0 of 8 placebo subjects (P = .312). In the open-label follow-up, headaches were relieved in 129 (41.2%) of 313 episodes within 15 minutes and in 141 (57.6%) of 245 episodes after 30 minutes. Headaches relapsed in 28 (19.9%) of 140. The response did not diminish over time: 32 (62.8%) of 51 first headaches were relieved at 30 minutes and 10 (71.4%) of 14 seventh headaches were relieved. Relapse occurred in 28 (41.2%) of 129 headaches at a mean time (+/- SD) of 7.4 (+/- 6.6) hours. CONCLUSION: Intranasal lidocaine 4% provides rapid relief of migraine symptoms. For those subjects who do respond, the effect does not diminish over 6-month follow-up.

Maizels, M., B. Scott, et al. (1996). "Intranasal lidocaine for treatment of migraine: a randomized, double-blind, controlled trial." Jama 276(4): 319-21.

            OBJECTIVE: To evaluate the effectiveness of intranasal lidocaine for treatment of acute migraine headache. DESIGN: Prospective, randomized, double-blind, placebo-controlled trial. SETTING: Community urgent care department. PATIENTS: A total of 81 patients (67 women and 14 men; median age, 42 years; range, 19-68 years) with a chief complaint of headache who fulfilled criteria of the International Headache Society for migraine participated. Patients were excluded if headache had lasted more than 3 days or if the frequency of severe headache was more than once per week. INTERVENTION: Patients were randomized in a 2:1 ratio to receive a 4 percent solution of intranasal lidocaine or saline placebo, respectively. MAIN OUTCOME MEASURES: The primary outcome measure was at least 50 percent reduction of headache within 15 minutes after treatment. Secondary measures include reduction in nausea and photophobia, use of rescue medication, relapse of headache, and change in headache disability scores. RESULTS: Of 53 patients who received intranasal lidocaine, 29 (55 percent) had at least a 50 percent reduction of headache compared with 6 (21 percent) of 28 controls (P=.004). Nausea and photophobia were significantly reduced (P=.03 and P=.001, respectively). Rescue medication for headache relief was needed in 15 (28 percent) of 53 patients in the lidocaine group vs 20 (71 percent) of 28 controls (P&lt;.001). Among those with initial relief of headache, relapse of headache occurred in 10 (42 percent) of 24 in the lidocaine group vs 5 (83 percent) of 6 in the control group (P=.17), usually within the first hour after treatment. CONCLUSIONS: Intranasal lidocaine provides rapid relief of headache in approximately 55 percent of ambulatory patients with migraine. Relapse of headache is common and occurs early after treatment.

Maizels, M., B. Scott, et al. (1996). "Intranasal lidocaine for treatment of migraine: a randomized, double-blind, controlled trial [see comments]." Jama 276(4): 319-21.

            OBJECTIVE: To evaluate the effectiveness of intranasal lidocaine for treatment of acute migraine headache. DESIGN: Prospective, randomized, double-blind, placebo-controlled trial. SETTING: Community urgent care department. PATIENTS: A total of 81 patients (67 women and 14 men; median age, 42 years; range, 19-68 years) with a chief complaint of headache who fulfilled criteria of the International Headache Society for migraine participated. Patients were excluded if headache had lasted more than 3 days or if the frequency of severe headache was more than once per week. INTERVENTION: Patients were randomized in a 2:1 ratio to receive a 4 percent solution of intranasal lidocaine or saline placebo, respectively. MAIN OUTCOME MEASURES: The primary outcome measure was at least 50 percent reduction of headache within 15 minutes after treatment. Secondary measures include reduction in nausea and photophobia, use of rescue medication, relapse of headache, and change in headache disability scores. RESULTS: Of 53 patients who received intranasal lidocaine, 29 (55 percent) had at least a 50 percent reduction of headache compared with 6 (21 percent) of 28 controls (P=.004). Nausea and photophobia were significantly reduced (P=.03 and P=.001, respectively). Rescue medication for headache relief was needed in 15 (28 percent) of 53 patients in the lidocaine group vs 20 (71 percent) of 28 controls (P&lt;.001). Among those with initial relief of headache, relapse of headache occurred in 10 (42 percent) of 24 in the lidocaine group vs 5 (83 percent) of 6 in the control group (P=.17), usually within the first hour after treatment. CONCLUSIONS: Intranasal lidocaine provides rapid relief of headache in approximately 55 percent of ambulatory patients with migraine. Relapse of headache is common and occurs early after treatment.

Markley, H. G. (2003). "Topical agents in the treatment of cluster headache." Curr Pain Headache Rep 7(2): 139-43.

            This article discusses topical intranasal medications in the treatment of cluster headache.

McGirr, A., M. T. Berlim, et al. (2014). "A systematic review and meta-analysis of randomized, double-blind, placebo-controlled trials of ketamine in the rapid treatment of major depressive episodes." Psychol Med: 1-12.

BACKGROUND: There is growing interest in glutamatergic agents in depression, particularly ketamine, a glutamate N-methyl-d-aspartate (NMDA) receptor antagonist. We aimed to assess the efficacy of ketamine in major depressive episodes. METHOD: We searched EMBASE, PsycINFO, CENTRAL, and Medline from 1962 to January 2014 to identify double-blind, randomized controlled trials with allocation concealment evaluating ketamine in major depressive episodes. Clinical remission, response and depressive symptoms were extracted by two independent raters. The primary outcome measure was clinical remission at 24 h, 3 days and 7 days post-treatment. Analyses employed a random-effects model. RESULTS: Data were synthesized from seven RCTs employing an intravenous infusion and one RCT employing intranasal ketamine, representing 73 subjects in parallel arms and 110 subjects in cross-over designs [n = 34 with bipolar disorder (BD), n = 149 with major depressive disorder (MDD)]. Ketamine was associated with higher rates of clinical remission relative to comparator (saline or midazolam) at 24 h [OR 7.06, number needed to treat (NNT) = 5], 3 days (OR 3.86, NNT = 6), and 7 days (OR 4.00, NNT = 6), as well as higher rates of clinical response at 24 h (OR 9.10, NNT = 3), 3 days (OR 6.77, NNT = 3), and 7 days (OR 4.87, NNT = 4). A standardized mean difference of 0.90 in favor of ketamine was observed at 24 h based on depression rating scale scores, with group comparisons revealing greater efficacy in unipolar depression compared to bipolar depression (1.07 v. 0.68). Ketamine was associated with transient psychotomimetic effects, but no persistent psychosis or affective switches. CONCLUSION: Our meta-analysis suggests that single administrations ketamine are efficacious in the rapid treatment of unipolar and bipolar depression. Additional research is required to determine optimal dosing schedules, route, treatment schedules, and the potential efficacy of other glutamatergic agents.

Miller, J. L., J. W. Ashford, et al. (2008). "Comparison of intranasal administration of haloperidol with intravenous and intramuscular administration: a pilot pharmacokinetic study." Pharmacotherapy 28(7): 875-882.

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.

Mills, T. M. and J. A. Scoggin (1997). "Intranasal lidocaine for migraine and cluster headaches." Ann Pharmacother 31(7-8): 914-5.

            While lidocaine may not be effective for the relief of all cluster or migraine headaches and the pain may recur in some patients, this therapy may offer an important therapeutic alternative for certain migraine patients. Further research may provide more information, such as which headache types best respond to lidocaine, if higher concentrations of lidocaine are more effective, if lidocaine solution is more effective than lidocaine nose spray, and if other local anesthetics are as effective.

McGirr, A., M. T. Berlim, et al. (2015). "A systematic review and meta-analysis of randomized, double-blind, placebo-controlled trials of ketamine in the rapid treatment of major depressive episodes." Psychol Med 45(4): 693-704.

BACKGROUND: There is growing interest in glutamatergic agents in depression, particularly ketamine, a glutamate N-methyl-d-aspartate (NMDA) receptor antagonist. We aimed to assess the efficacy of ketamine in major depressive episodes. METHOD: We searched EMBASE, PsycINFO, CENTRAL, and Medline from 1962 to January 2014 to identify double-blind, randomized controlled trials with allocation concealment evaluating ketamine in major depressive episodes. Clinical remission, response and depressive symptoms were extracted by two independent raters. The primary outcome measure was clinical remission at 24 h, 3 days and 7 days post-treatment. Analyses employed a random-effects model. RESULTS: Data were synthesized from seven RCTs employing an intravenous infusion and one RCT employing intranasal ketamine, representing 73 subjects in parallel arms and 110 subjects in cross-over designs [n = 34 with bipolar disorder (BD), n = 149 with major depressive disorder (MDD)]. Ketamine was associated with higher rates of clinical remission relative to comparator (saline or midazolam) at 24 h [OR 7.06, number needed to treat (NNT) = 5], 3 days (OR 3.86, NNT = 6), and 7 days (OR 4.00, NNT = 6), as well as higher rates of clinical response at 24 h (OR 9.10, NNT = 3), 3 days (OR 6.77, NNT = 3), and 7 days (OR 4.87, NNT = 4). A standardized mean difference of 0.90 in favor of ketamine was observed at 24 h based on depression rating scale scores, with group comparisons revealing greater efficacy in unipolar depression compared to bipolar depression (1.07 v. 0.68). Ketamine was associated with transient psychotomimetic effects, but no persistent psychosis or affective switches. CONCLUSION: Our meta-analysis suggests that single administrations ketamine are efficacious in the rapid treatment of unipolar and bipolar depression. Additional research is required to determine optimal dosing schedules, route, treatment schedules, and the potential efficacy of other glutamatergic agents.

Ormrod, D. and K. L. Goa (1999). "Intranasal metoclopramide." Drugs 58(2): 315-22; discussion 323-4.

            Intranasal metoclopramide is a new formulation of an established and effective antiemetic drug. Absorption after intranasal administration was lower than after oral or intravenous administration; otherwise the pharmacodynamic and pharmacokinetic profiles of the intranasal and parenteral formulations were similar. Intranasal and intramuscular metoclopramide showed similar efficacy in the control of acute emesis induced by moderately emetogenic chemotherapy in 12 patients. Intranasal metoclopramide 80mg significantly reduced the frequency of acute vomiting in 43 patients receiving highly emetogenic chemotherapy. A pilot study suggested that intranasal metoclopramide, with or without dexamethasone, may reduce cisplatin-induced delayed emesis. In a randomised crossover trial in 40 patients, intranasal metoclopramide or oral metoclopramide, both with dexamethasone, were equally effective in the control of delayed emesis induced by moderately-emetogenic chemotherapy. One 30 patient study suggests that intranasal metoclopramide has similar efficacy to oral metoclopramide in the treatment of functional dyspepsia. A non-significant trend to reducing postoperative nausea and vomiting has been seen in two trials of intranasal metoclopramide. Intranasal metoclopramide caused minor irritation of the nasal membrane and unpleasant taste in some patients, but was otherwise well tolerated. None of the more serious extrapyramidal effects sometimes associated with metoclopramide were reported.

Papolos, D. F., M. H. Teicher, et al. (2013). "Clinical experience using intranasal ketamine in the treatment of pediatric bipolar disorder/fear of harm phenotype." J Affect Disord 147(1-3): 431-436.

                OBJECTIVES: Intravenous ketamine, a glutamate N-methyl-d-aspartate (NMDA) receptor antagonist, has been shown to exert a rapid antidepressant effect in adults with treatment resistant depression. Children with bipolar disorder (BD) often respond poorly to pharmacotherapy, including polypharmacy. A pediatric-onset Fear of Harm (FOH) phenotype has been described, and is characterized by severe clinical features and resistance to accepted treatments for BD. The potential efficacy and safety of intranasal ketamine in children with BD with FOH-phenotype were assessed by a systematic retrospective chart review of a case series from the private practice of one of the authors, including cases with clear refractoriness to mood stabilizers, antipsychotics and benzodiazepines. METHODS: A comparison was made between routinely collected symptom measures 1-2 weeks prior to and after the administration of ketamine, in 12 treatment-refractory youth, 10 males 2 females ages 6-19years. RESULTS: Ketamine administration was associated with a substantial reduction in measures of mania, fear of harm and aggression. Significant improvement was observed in mood, anxiety and behavioral symptoms, attention/executive functions, insomnia, parasomnias and sleep inertia. Treatment was generally well-tolerated. CONCLUSIONS: Intranasal ketamine administration in treatment-resistant youth with BD-FOH produced marked improvement in all symptomatic dimensions. A rapid, substantial therapeutic response, with only minimal side effects was observed. Formal clinical trials to assess safety and efficacy are warranted.

Parkman, H. P., M. R. Carlson, et al. (2014). "Metoclopramide nasal spray is effective in symptoms of gastroparesis in diabetics compared to conventional oral tablet." Neurogastroenterol Motil 26(4): 521-528.

BACKGROUND: Delayed gastric emptying symptoms interfere with the absorption of oral medications. Intranasal metoclopramide is being developed as an alternative to oral metoclopramide for patients with diabetic gastroparesis. METHODS: To compare the efficacy and safety of metoclopramide nasal spray to oral tablets in diabetic patients with symptoms of gastroparesis, this randomized, open-label, parallel design study randomized subjects to 10 or 20 mg nasal spray or 10 mg tablet four times a day for 6 weeks. Efficacy was evaluated using a total symptom score (TSS). KEY RESULTS: Eighty-nine subjects were enrolled. For the intention to treat population, both nasal dose groups (10 and 20 mg) had lower TSS with treatment compared to the oral 10 mg group. The change from baseline in TSS for nasal 20 mg was greater than the oral 10 mg at Week 6 (p = 0.026). For the per-protocol population, there was a significant difference in the TSS between baseline and Week 6 for both the nasal 10 mg (p = 0.026) and the nasal 20 mg (p = 0.008) cohorts compared to the oral 10 mg group. Based on the definition of a responder, 88.9% of subjects who received oral 10 mg, 91.2% who received nasal 10 mg, and 97.1% who received nasal 20 metoclopramide were classified as responders. The side-effect profile of the metoclopramide nasal spray was favorable. More side effects, especially nausea, occurred with the oral tablets. CONCLUSIONS & INFERENCES: Metoclopramide nasal spray offers better symptom control than metoclopramide oral tablet in diabetic patients with symptoms of gastroparesis.

Pedersen, C. A., K. L. Smedley, et al. (2013). "Intranasal oxytocin blocks alcohol withdrawal in human subjects." Alcohol Clin Exp Res 37(3): 484-489.

BACKGROUND: The neuropeptide, oxytocin (OT), has been reported to block tolerance formation to alcohol and decrease withdrawal symptoms in alcohol-dependent rodents. Numerous recent studies in human subjects indicate that OT administered by the intranasal route penetrates into and exerts effects within the brain. METHODS: In a randomized, double-blind clinical trial, intranasal OT (24 IU/dose, N = 7) or placebo (N = 4) was given twice daily for 3 days in alcohol-dependent subjects admitted to a research unit for medical detoxification using Clinical Institute Withdrawal Assessment for Alcohol (CIWA) score-driven PRN administration of lorazepam. Subjects rated themselves on the Alcohol Withdrawal Symptom Checklist (AWSC) each time CIWA scores were obtained. Subjects also completed the Penn Alcohol Craving Scale, an Alcohol Craving Visual Analog Scale (ACVAS) and the Profile of Mood States (POMS) on inpatient days 2 and 3. RESULTS: All subjects had drunk heavily each day for at least 2 weeks prior to study and had previously experienced withdrawal upon stopping/decreasing alcohol consumption. OT was superior to placebo in reducing alcohol withdrawal as evidenced by: less total lorazepam required to complete detoxification (3.4 mg [4.7, SD] vs. 16.5 [4.4], p = 0.0015), lower mean CIWA scores on admission day 1 (4.3 [2.3] vs. 11.8 [0.4], p < 0.0001) and day 2 (3.4 [2.2] vs. 11.1 [3.6], p < 0.002), lower AWSC scores on days 1 and 2 (p < 0.02; p = 0.07), and lower ACVAS ratings (p = 0.01) and lower POMS Tension/Anxiety subscale scores on day 2 (p < 0.01). CONCLUSIONS: This is the first demonstration that OT treatment may block alcohol withdrawal in human subjects. Our results are consistent with previous findings in rodents that OT inhibits neuroadaptation to and withdrawal from alcohol. OT could have advantages over benzodiazepines in managing alcohol withdrawal because it may reverse rather than maintain sedative-hypnotic tolerance. It will be important to test whether OT treatment is effective in reducing drinking in alcohol-dependent outpatients.

Piazza, J., T. Hoare, et al. (2014). "Haloperidol-loaded intranasally administered lectin functionalized poly(ethylene glycol)-block-poly(D,L)-lactic-co-glycolic acid (PEG-PLGA) nanoparticles for the treatment of schizophrenia." Eur J Pharm Biopharm 87(1): 30-39.

Lectin-functionalized, polyethylene glycol-block-poly-(D,L)-lactic-co-glycolic acid nanoparticles loaded with haloperidol were prepared with narrow size distributions and sizes <135nm. The nanoparticles exhibited high Solanum tuberosum lectin (STL) conjugation efficiencies, encapsulation efficiencies, and drug loading capacities. The in vitro release of haloperidol was 6-8% of the loaded amount in endo-lysosomal conditions over 96h, demonstrating minimal drug leakage and the potential for the efficient drug transport to the targeted brain tissue. The haloperidol released upon erosion was successful in displacing [(3)H] N-propylnorapomorphine and binding to bovine striatal dopamine D2 receptors. Both haloperidol-loaded nanoparticle formulations were found to be highly effective at inducing catalepsy. Intranasal administration of STL-functionalized nanoparticles increased the brain tissue haloperidol concentrations by 1.5-3-fold compared to non-STL-functionalized particles and other routes of administration. This formulation demonstrates promise in the reduction of the drug dose necessary to produce a therapeutic effect with antipsychotic drugs for the treatment of schizophrenia.

Quadir, M., H. Zia, et al. (2000). "Development and evaluation of nasal formulations of ketorolac." Drug Deliv 7(4): 223-9.

            Ketorolac tromethamine is a potent non-narcotic analgesic with moderate anti-inflammatory activity. Clinical studies indicate that ketorolac has a single dose efficacy greater than morphine for postoperative pain and has excellent applicability in the emergency treatment of pain. Due to incomplete oral absorption of ketorolac, several approaches have been tried to develop a nonoral formulation in addition to injections, especially for the treatment of migraine headache. The aim of our study was to develop a nasal formulation of ketorolac with a dose equivalent to the oral formulation. A series of spray and lyophilized powder formulations of ketorolac were administered into the nasal cavity of rabbits, and their pharmacokinetics profiles were assessed. The spray and powder formulations were compared through their pharmacokinetics parameters and absolute bioavailability. Drug plasma concentration was determined using solid phase extraction, followed by an HPLC analysis. Nasal spray formulations were significantly better absorbed than powder formulations. A nasal spray formulation of ketorolac tromethamine showed the highest absorption with an absolute bioavailability of 91%. Within 30 min of administration, the plasma concentration was comparable to that resulting from an intravenous injection. The absolute bioavailability of a solution of ketorolac acid was 70%. Apparently, the dissolution of ketorolac acid into the mucous layer limits its absorption. There were no significant differences in absorption between different powder formulations. Even the reduction of particle size from 123 microm to 63 microm did not indicate better absorption of ketorolac tromethamine from powder formulations. Interestingly, the absolute bioavailability of ketorolac tromethamine from a powder formulation is only 38%, indicating that the drug may not be totally released from the polymer matrix before it is removed from nasal epithelium by mucociliary clearance.

Rapoport, A. and P. Winner (2006). "Nasal delivery of antimigraine drugs: clinical rationale and evidence base." Headache 46 Suppl 4: S192-201.

            The intranasal route of administration for antimigraine drugs offers many theoretical and practical advantages. A drug that is administered intranasally is absorbed by the highly vascular mucous membranes of the nose, which allows for rapid delivery of un-metabolized drug to the central nervous system. The onset of action is thus considerably earlier than with oral administration requiring gastrointestinal absorption. The intranasal route also provides several practical advantages, such as greater acceptability to patients because of the noninvasive mode of delivery, the ability to take medication when severe nausea or vomiting is present, and a better adverse event profile. Three antimigraine drugs are available in intranasal formulation: dihydroergotamine, sumatriptan, and zolmitriptan. This article reviews the pharmacology, efficacy, safety, and tolerability of these agents. All are well tolerated by patients and have demonstrated efficacy in the treatment of migraine headache. Each of these drugs has a unique pharmacokinetic and pharmacodynamic profile, which may support a clinical preference for one intranasal agent over another in treating patients with specific headache features.

Rapoport, A. M., M. E. Bigal, et al. (2004). "Intranasal medications for the treatment of migraine and cluster headache." CNS Drugs 18(10): 671-85.

            Intranasal medications for the treatment of headache have recently received increased attention. This paper reviews intranasal formulations of a variety of available medications (dihydroergotamine mesylate [dihydroergotamine mesilate], sumatriptan, zolmitriptan, butorphanol, capsaicin and lidocaine [lignocaine]) and one experimental medication (civamide, a cis-isomer of capsaicin) for the treatment of migraine and cluster headache. Although the efficacy of intranasal agents varies with the product used, intranasal delivery may be both convenient and more effective than other modes of drug delivery for a variety of reasons: (i) intranasal administration bypasses small bowel gastrointestinal tract absorption, which is often significantly delayed during the acute phase of a migraine attack; (ii) nauseated patients may prefer non-oral formulations as they decrease the chance of vomiting and are more rapidly effective; (iii) intranasal administration causes no pain or injection site reaction and is easier and more convenient to administer than injection or suppository and so may be used earlier in a migraine attack, resulting in better efficacy; (iv) intranasal medication produces the same number or fewer adverse events than injections; and (v) intranasal formulations offer a more rapid onset of action than oral medications, for some of the above reasons and, as such, may be more useful in patients with cluster headache, although this needs to be verified. However, it is important to emphasise that a preference study showed that most patients prefer oral tablets to an intranasal formulation. Also, some nasal preparations have significant adverse effects or are not well absorbed and therefore do not work consistently; others are more challenging to administer as a result of their delivery apparatus. Nevertheless, it is our opinion that nasal preparations increase therapeutic options and may result in faster response times and better efficacy than oral formulations and better patient satisfaction than injectable preparations.

Rash, J. A. and T. S. Campbell (2014). "The effect of intranasal oxytocin administration on acute cold pressor pain: a placebo-controlled, double-blind, within-participants crossover investigation." Psychosom Med 76(6): 422-429.

BACKGROUND: This study examined the effect of synthetic oxytocin delivered intranasally on acute pain sensitivity using a placebo-controlled, double-blind, within-participant crossover design. METHODS: Thirty-seven (18 were male) pain-free young adults underwent two laboratory sessions separated by 1 week. Each session consisted of baseline, administration, second baseline, pain, and recovery phases, completed in a fixed order. Participants were given an intransal administration of 40 IU oxytocin or placebo. Blood pressure and heart rate (HR) were measured at 1-minute intervals throughout each phase. Pain was induced by submersing the nondominant hand in cold (2 degrees C) water. Pain threshold, intensity, unpleasantness, and Short-Form McGill Pain Questionnaire-2 pain descriptors were rated immediately after pain testing. Mood was assessed using visual analog scales after baseline, second baseline, and pain phases. The second laboratory session was identical to the first, with the exception that a different nasal spray was administered. RESULTS: Participants reported lower pain intensity (50.57 [20.94] versus 56.73 [20.12], p = .047), pain unpleasantness (47.00 [27.24] versus 55.78 [22.46], p = .033), and Short-Form McGill Pain Questionnaire-2 pain descriptors (53.38 [31.18] versus 60.92 [31.17], p = .031) and higher pain threshold (45.70 [59.55] versus 38.35 [59.12], p = .040) after oxytocin administration relative to placebo. There was a nasal spray by phase interaction on HR (p = .006). Pain-related increase in HR was attenuated by oxytocin nasal spray. Systolic and diastolic blood pressure increased during pain testing but were unaffected by nasal spray. CONCLUSIONS: These results suggest that oxytocin can lead to decreased acute pain sensitivity.

Robbins, L. (1995). "Intranasal lidocaine for cluster headache." Headache 35(2): 83-4.

            Thirty male patients with cluster headache were given 4% lidocaine solution to use intranasally as an abortive therapy. Four sprays of lidocaine were used ipsilateral to the pain, and two more were used, if necessary. Twenty-seven percent of the men reported moderate relief, 27% obtained mild relief, and 46% stated that they had no relief from the lidocaine, Side effects were minimal. In this study, intranasal lidocaine was only a marginally helpful therapy for cluster headache. However, because of the ease of administration and lack of side effects, lidocaine may remain worthwhile as an adjunctive medication.

Slot, W. B., F. W. Merkus, et al. (1997). "Normalization of plasma vitamin B12 concentration by intranasal hydroxocobalamin in vitamin B12-deficient patients." Gastroenterology 113(2): 430-3.

            BACKGROUND & AIMS: Patients with previous stomach and terminal ileum resections are often treated with intramuscular vitamin B12 injections. Disadvantages are, on a worldwide scale, the frequent need for medical personnel to administer injections and the sometimes painful way of application. This study was designed to investigate the feasibility of intranasal hydroxocobalamin suppletion in cobalamin-deficient patients and to assess whether intranasal hydroxocobalamin application could be an alternative for intramuscular injection. METHODS: Six patients with plasma cobalamin concentrations of < 200 ng/L were recruited. A dose of 1500 micrograms hydroxocobalamin was applied intranasally at days 0, 14, and 21. Plasma cobalamin concentrations were determined 1 hour after hydroxocobalamin application and on days 0, 7, 21, 28, and 35. RESULTS: All patients showed substantial increase of cobalamin concentrations 1 hour after intranasal application. In these 6 patients, there was an eightfold increase of mean baseline cobalamin concentrations. All patients showed a sustained increase of baseline cobalamin concentrations 1 week after prior intranasal application of hydroxocobalamin. No side effects were noted. CONCLUSIONS: Intranasal application of hydroxocobalamin in cobalamin-deficient patients results in fast nasal absorption and leads to sustained increase of baseline cobalamin concentrations.

Tomirotti, M., M. Dimaiuta, et al. (1994). "Efficacy and tolerability of nasally administered compared to parenterally administered metoclopramide in the symptomatic treatment of chemotherapy-induced emesis in cancer outpatients. A controlled clinical study." Support Care Cancer 2(6): 389-92.

            The clinical efficacy and tolerability of a new nasal spray formulation of metoclopramide (MTC) was evaluated in terms of its ability to prevent the nausea and vomiting induced by a moderately emetic chemotherapy (cisplatin 20 mg/m2 weekly as radioenhancer+radiotherapy for a fractionated total of 60 Gy) in 12 patients with non-small-cell lung cancer, stage IIIB. The first chemotherapy cycle was administered without any prophylaxis in order to identify those patients who experienced grade 2 nausea and/or vomiting. As prophylaxis during the second cycle, these patients were given MTC 20 mg i.v. at time zero, and MTC 20 mg i.m. after 4 h and 8 h; during the third cycle, they received MTC 40 mg by nasal spray 2 h before chemotherapy, followed by the same dose at 4 h and 8 h. The two prophylactic treatments (parenteral injections and nasal spray) proved to be therapeutically equivalent: complete protection, 6 and 6 patients respectively; major protection, 2 and 3 patients; minor protection, 1 and 1 patient; no protection, 3 and 2 patients. The control of nausea was satisfactory, with 7 and 9 patients respectively experiencing grade 0-1 nausea. Comparative analysis of individual responses confirmed the similar anti-emetic efficacy of the two regimens. No adverse reactions were observed at any time during the course of the study, and all 12 patients judged the acceptability of the new formulation as optimal. It can thus be concluded that the use of metoclopramide nasal spray represents an effective, safe, easily managed and low-cost therapeutic alternative for the prophylaxis and treatment of emesis induced by low-dose chemotherapy.(ABSTRACT TRUNCATED AT 250 WORDS)

van Asselt, D. Z., F. W. Merkus, et al. (1998). "Nasal absorption of hydroxocobalamin in healthy elderly adults." Br J Clin Pharmacol 45(1): 83-6.

            AIMS: To investigate the nasal absorption of hydroxocobalamin in 10 healthy elderly adults. METHODS: In a cross-over study, blood samples were collected before administration of the drug and after 10, 20, 30, 40, 60, 120, 180 and 240 min. The plasma cobalamin concentration was determined by competitive radioisotope binding technique. RESULTS: The maximal plasma cobalamin concentration (Cmax) after nasal administration of 750 microg hydroxocobalamin was 1900 +/- 900 pmol l(-1) (mean +/- s.d.). The maximal plasma cobalamin concentration was reached in 35 +/- 13 min (t[max]). The Cmax after nasal administration of 1500 microg hydroxocobalamin was 3500 +/- 2500 pmol l(-1) with a t(max) of 28 +/- 16 min. Both the AUC(0,240 min) and AUC(0,00) increased significantly with an increase of the dose from 750 microg to 1500 microg (P = 0.037 and P = 0.028, respectively). The nasal spray was well tolerated. No signs of irritation or local sensitivity were noted. CONCLUSIONS: The nasal absorption of hydroxocobalamin in healthy elderly adults is rapid, high and well tolerated.

 

van der Kuy, P. H., F. W. Merkus, et al. (2002). "Hydroxocobalamin, a nitric oxide scavenger, in the prophylaxis of migraine: an open, pilot study." Cephalalgia 22(7): 513-9.

            Drugs which directly counteract nitric oxide (NO), such as endothelial receptor blockers, NO-synthase inhibitors, and NO-scavengers, may be effective in the acute treatment of migraine, but are also likely to be effective in migraine prophylaxis. In the underlying pilot study the prophylactic effect of the NO scavenger hydroxocobalamin after intranasal administration in migraine was evaluated. Twenty patients, with a history of migraine of > 1 year and with two to eight migraine attacks per month, were included in an open trial. A baseline period was followed by an active treatment period of 3 months with 1 mg intranasal hydroxocobalamin daily. Patients were instructed to complete a diary in which details of each attack were described. A reduction in migraine attack frequency of >/ or = 50% was seen in 10 of 19 patients, which corresponds to 53% of the patients (responders). A reduction of > or = 30% was noted in 63% of the patients. The mean attack frequency in the total study population showed a reduction from 4.7 +/- 1.7 attacks per month to 2.7 +/- 1.6 (P < 0.001). For the responders the migraine attack frequency was reduced from 5.2 +/- 1.9 (baseline) to 1.9 +/- 1.3 attacks per month (P < 0.005), while for those who did not respond a non-significant reduction was found: 4.1 +/- 1.4 to 3.7 +/- 1.5 (P > 0.1). A reduction was also observed for the total duration of the migraine attacks per month, the total number of migraine days per month and the number of medication doses for acute treatment used per month. This is the first prospective, open study indicating that intranasal hydroxocobalamin may have a prophylactic effect in migraine. As a percentage of responders in prophylactic trials of > 35-40% is unlikely to be a placebo effect, a double-blind study is warranted.

Wagner, B. K., S. L. Berman, et al. (1996). "A double-blind, placebo-controlled evaluation of intranasal metoclopramide in the prevention of postoperative nausea and vomiting." Pharmacotherapy 16(6): 1063-9.

            Nausea and vomiting are common complaints in the postoperative period and contribute to patient distress and delay of discharge for outpatient surgical procedures. Laparoscopic procedures are associated with a high incidence of postoperative nausea and vomiting (PONV) episodes. Parenteral use of metoclopramide prevents and treats PONV. The intranasal route provides rapid and complete absorption of metoclopramide without many of the adverse effects observed with parenteral administration of the drug. We performed a prospective, double-blinded, randomized, placebo-controlled study to evaluate the safety and efficacy of metoclopramide 20 mg administered intranasally for emetic prophylaxis in laparoscopic surgery patients. The results from 109 patients enrolled in the study showed that this intranasal dose of metoclopramide may be ineffective in preventing the occurrence of PONV. The poor performance of the intranasal metoclopramide formulation in this study cannot be attributed to patient-specific and perioperative factors. It may be due to an inadequate dose or slow absorption of the drug. The small sample size, however, may also have been a factor.

Weintraub, J. (2006). "Repetitive dihydroergotamine nasal spray for treatment of refractory headaches: an open-label pilot study." Curr Med Res Opin 22(10): 2031-6.

            OBJECTIVE: To evaluate the safety and efficacy of a repetitive intranasal (IN) dihydroergotamine (DHE) burst protocol for treatment of refractory headaches. RESEARCH DESIGN AND METHODS: Patients with refractory headaches were enrolled in a prospective, open-label, pilot study. Patients were instructed to self-administer IN DHE every 8 hours for 3 days; each IN DHE dose consisted of one 0.5-mg spray in each nostril that was repeated 15 minutes later, for a total of 2.0 mg DHE per dose. Follow-up visits were scheduled approximately 3 weeks later. MAIN OUTCOME MEASURES: Efficacy and safety measurements were collected during patient interviews. Primary efficacy measures were the change in headache frequency, duration, and severity (rated from 0 [none] to 5 [extremely severe]) between the initial and follow-up visits. Safety was assessed at the follow-up visits through the occurrence of adverse events (AEs). RESULTS: Twenty-six patients were enrolled in the study. Follow-up visits were completed by 24 patients whose mean headache frequency at study entry was 6.6 d/wk. The IN DHE burst protocol was associated with significant mean decreases in headache frequency (2.6 d/wk, p < 0.001), duration (5.8 hours, p = 0.03), and severity (1.2 units, p < 0.001) between study entry and the follow-up visit. One patient discontinued IN DHE use early because of an AE (nasal stuffiness); two additional patients each reported one AE (fatigue and increased headache) that was attributed to IN DHE. CONCLUSIONS: The results of this pilot study suggest that the IN DHE burst protocol may be an effective and safe treatment for refractory headaches; interpretation of these results is limited by the open-label, uncontrolled design and the small number of patients. The development of a double-blind, placebo-controlled study to further evaluate this treatment regimen is warranted.

Weksler, N., S. Brill, et al. (1999). "Intranasal salbutamol instillation in asthma attack." Am J Emerg Med 17(7): 686-688.

Beta-two sympathomimetic drugs are the treatment of choice for asthmatic attack. Their main effect is to dilate the bronchi by a direct action on beta-two adrenoreceptors on the smooth muscle, and also by mediator release inhibition from mast cells. Salbutamol is widely used in the treatment of bronchial asthma, and is usually administered either by inhalation, orally, or parenterally. The nasal route seems to afford an effective way to administer medications, since the nasal mucosa has a relatively large surface area, and there is no gastrointestinal-hepatic first pass-effect, thus avoiding extensive loss of the administered drug. We describe herein the use of nasal salbutamol in 3 patients with severe asthma attacks who were refractory to conventional therapy, with favorable responses and without significant undesirable effects.

Zeppetella, G. (2000). "An assessment of the safety, eff icacy, and acceptability of intranasal fentanyl citrate in the management of cancer-related breakthrough pain. A pilot study." J Pain Symptom Manage 20(4): 253-8.

            The effects of intranasal fentanyl citrate (INFC) were assessed in 12 hospice inpatients with cancer-related breakthrough pain. Patients received 20 &amp;mgr;g of fentanyl citrate and were asked to rate their pain using a visual analogue scale (VAS) before INFC, then after 3, 5, 10, 15, 30, 45, and 60 minutes. Eight patients (66%) had reductions in pain scores, four within 5 minutes and seven within 10 minutes of taking INFC. Ratings for INFC were very good (5 = 42%), good (3 = 25%), moderate (1 = 8%), and bad (3 = 25%). In comparison to oral morphine, INFC was better (6 = 50%), the same (3 = 25%), or worse (3 = 25%). Nine patients (75%) said they would continue to use INFC. Of the three patients who did not experience a positive result, two were taking relatively higher baseline opioid doses and one was found to have a fracture. No systemic adverse events were noted; two patients reported nasal itching or discomfort on first use that disappeared with repeated use. Intranasal fentanyl citrate appears safe and well tolerated by these patients. Randomized placebo-controlled and dose-ranging studies are required to confirm these findings.