Seizing child recieving IN treatmentTherapeutic Intranasal Drug Delivery

Needleless treatment options for medical problems

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Intranasal  Medications in Hospice and Palliative care -     abstracted references:

Ahmad, S., J. C. Ellis, et al. (2006). "Efficacy and safety of intranasal lorazepam versus intramuscular paraldehyde for protracted convulsions in children: an open randomised trial." Lancet 367(9522): 1591-7.

            BACKGROUND: In sub-Saharan Africa, rectal diazepam or intramuscular paraldehyde are commonly used as first-line anticonvulsant agents in the emergency treatment of seizures in children. These treatments can be expensive and sometimes toxic. We aimed to assess a drug and delivery system that is potentially more effective, safer, and easier to administer than those presently in use. METHODS: We did an open randomised trial in a paediatric emergency department of a tertiary hospital in Malawi. 160 children aged over 2 months with seizures persisting for more than 5 min were randomly assigned to receive either intranasal lorazepam (100 microg/kg, n=80) or intramuscular paraldehyde (0.2 mL/kg, n=80). The primary outcome measure was whether the presenting seizure stopped with one dose of assigned anticonvulsant agent within 10 min of administration. The primary analysis was by intention-to-treat. This study is registered with, number NCT00116064. FINDINGS: Intranasal lorazepam stopped convulsions within 10 min in 60 (75%) episodes treated (absolute risk 0.75, 95% CI 0.64-0.84), and intramuscular paraldehyde in 49 (61.3%; absolute risk 0.61, 95% CI 0.49-0.72). No clinically important cardiorespiratory events were seen in either group (95% binomial exact CI 0-4.5%), and all children finished the trial. INTERPRETATION: Intranasal lorazepam is effective, safe, and provides a less invasive alternative to intramuscular paraldehyde in children with protracted convulsions. The ease of use of this drug makes it an attractive and preferable prehospital treatment option.

Carr, Db, et al. (2004). "Safety and efficacy of intranasal ketamine in a mixed population with chronic pain." Pain 110(3): 762-4.        

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.

Chien, Y. W., K. S. E. Su, et al. (1989). Chapter 1: Anatomy and Physiology of the Nose. Nasal Systemic Drug Delivery. Y. W. Chien, K. S. E. Su and S. F. Chang. New York, Marcel Dekker Inc,. : 1-26.

Coluzzi, P. H., L. Schwartzberg, et al. (2001). "Breakthrough cancer pain: a randomized trial comparing oral transmucosal fentanyl citrate (OTFC) and morphine sulfate immediate release (MSIR)." Pain 91(1-2): 123-30.

            Oral transmucosal fentanyl citrate (OTFC); Actiq) is a drug delivery formulation used for management of breakthrough cancer pain. Previous studies with open-label comparisons indicated OTFC was more effective than patients' usual opioid for breakthrough pain. The objective of this study was to compare OTFC and morphine sulfate immediate release (MSIR) for management of breakthrough pain in patients receiving a fixed scheduled opioid regimen. This double-blind, double-dummy, randomized, multiple crossover study was conducted at 19 US university- and community-based hospitals and clinics and comprised 134 adult ambulatory cancer patients. Patients were receiving a fixed scheduled opioid regimen equivalent to 60-1000 mg/day oral morphine or 50-300 microg/h transdermal fentanyl, were using a 'successful' MSIR dose (15-60 mg) as defined by entry criteria, and were experiencing 1-4 episodes of breakthrough pain per day. In open-label fashion, OTFC was titrated such that a single unit (200-1600 microg) provided adequate pain relief with acceptable side effects. Successfully titrated patients entered the double-blind phase of the study and received ten prenumbered sets of randomized capsules and oral transmucosal units. Five sets were the successful OTFC dose paired with placebo capsules, and five sets were placebo OTFC paired with capsules containing the successful MSIR dose. Patients took one set of study medication for each episode of target breakthrough pain. Pain intensity (PI), pain relief (PR) and global performance of medication (GP) scores were recorded. Pain intensity differences (PID) were calculated and 15-min PID was the primary efficacy variable. Adverse events were recorded. Sixty-nine percent of patients (93/134) found a successful dose of OTFC. OTFC yielded outcomes (PI, PID, and PR) at all time points that were significantly better than MSIR. GP also favored OTFC and more patients opted to continue with OTFC than MSIR following the study. Somnolence, nausea, constipation, and dizziness were the most common drug-associated side effects. In conclusion, OTFC was more effective than MSIR in treating breakthrough cancer pain.

Dale, O., R. Hjortkjaer, et al. (2002). "Nasal administration of opioids for pain management in adults." Acta Anaesthesiol Scand 46(7): 759-70.

            BACKGROUND: Nasal administration of opioids may be an alternative route to intravenous, subcutaneous, oral transmucosal, oral or rectal administration in some patients. Key features may be self-administration, combined with rapid onset of action. The aim of this paper is to evaluate the present base of knowledge on this topic. METHODS: The review is based on human studies found in Medline or in the reference list of these papers. The physiology of the nasal mucosa and some pharmaceutical aspects of nasal administration are described. The design of each study is described, but not systematically evaluated. RESULTS: Pharmacokinetic studies in volunteers are reported for fentanyl, alfentanil, sufentanil, butorphanol, oxycodone and buprenorphine. Mean times for achieving maximum serum concentrations vary from 5 to 50 min, while mean figures for bioavailability vary from 46 to 71%. Fentanyl, pethidine and butorphanol have been studied for postoperative pain. Mean onset times vary from 12 to 22 min and times to peak effect from 24 to 60 min. There is considerable interindividual variation in pharmacokinetics and clinical outcome. This may partly be due to lack of optimization of nasal formulations. Patient-controlled nasal analgesia is an effective alternative to intravenous PCA. Adverse effects are mainly those related to the opioids themselves, rather than to nasal administration. Some experience with nasal opioids in outpatients and for chronic pain has also been reported. CONCLUSION: Nasal administration of opioids has promising features, but is still in its infancy. Adequately designed clinical studies are needed. Improvements of nasal sprayer devices and opioid formulations may improve clinical outcome.

Denby, A. (2009). "Fentanyl preparations for breakthrough cancer pain." London New Drugs Group APC/DTC briefing August 2009: 1-9.


Farrar, J. T., J. Cleary, et al. (1998). "Oral transmucosal fentanyl citrate: randomized, double-blinded, placebo-controlled trial for treatment of breakthrough pain in cancer patients." J Natl Cancer Inst 90(8): 611-6.

            BACKGROUND: Patients with cancer frequently experience episodes of acute pain, i.e., breakthrough pain, superimposed on their chronic pain. Breakthrough pain is usually treated with short-acting oral opioids, most of which provide some relief after 15-20 minutes, with peak effects after 30-45 minutes. Oral transmucosal fentanyl citrate (OTFC), a unique formulation of the opioid fentanyl, has been shown to provide meaningful pain relief within 5 minutes in patients following surgery. We conducted a multicenter, randomized, double-blinded, placebo-controlled trial of OTFC for cancer-related breakthrough pain. METHODS: Patients who were 18 years of age or older, receiving the equivalent of at least 60 mg oral morphine or at least 50 microg transdermal fentanyl per day for chronic cancer-related pain, and experiencing at least one episode of breakthrough pain per day were studied. After titration to an effective OTFC dose, subjects were given 10 randomly ordered treatment units (seven OTFC units and three placebo units) in the form of identical lozenges. If acceptable pain relief was not achieved within 30 minutes, subjects were instructed to take their previous breakthrough pain medication (i.e., rescue medication). Pain intensity, pain relief, and use of rescue medication were evaluated at 15-minute intervals over a 60-minute period. RESULTS: Eighty-nine of 92 patients who received the randomized treatment were assessable (i.e., treated with at least one unit of OTFC and one unit of placebo). OTFC produced significantly larger changes in pain intensity and better pain relief than placebo at all time points (two-sided P<.0001). Episodes treated with placebo required the use of rescue medication more often than episodes treated with OTFC (34% versus 15%; relative risk = 2.27; 95% confidence interval = 1.51-3.26; two-sided P<.0001). CONCLUSIONS: OTFC appears effective in the treatment of cancer-related breakthrough pain.


Fukuta, O., R. L. Braham, et al. (1993). "The sedative effect of intranasal midazolam administration in the dental treatment of patients with mental disabilities. Part 1. The effect of a 0.2 mg/kg dose." J Clin Pediatr Dent 17(4): 231-7.

            The purpose of this study was to determine the sedative effect of a 0.2 mg/kg dose of midazolam, administered intranasally, prior to performing various restorative dental procedures on a group of mentally disabled patients under local anesthesia and nitrous oxide/oxygen analgesia. Twenty-one patients, aged 4 to 21 years, all of whom had previously exhibited highly combative and resistant behavior toward dental treatment under local anesthesia, were sedated with 0.2 mg/kg midazolam. Only patients assessed as ASA anesthesia status I or II were admitted to the study. After administering the midazolam, each patient was allowed to rest before initiating the dental procedures. Behavioral patterns during the various procedures were rated on a behavioral rating scale of 1-7. Each patient served as his or her own control, comparing behavior with or without intranasal midazolam. The results showed a marked improvement in behavioral patterns after administration of intranasal midazolam. Ratings on a scale of 1-7 were noted as &quot;markedly effective&quot; and &quot;effective&quot; for 69.2% of those patients who received infiltration injection anesthesia, 93.8% under rubber dam, 76.2% during cavity preparation, 84.2% for restoration placement and 87.5% during pulpotomy procedures. The majority of patients were discharged within 150 minutes of intranasal instillation. Further studies are indicated to ascertain the most appropriate dose of intranasally administered midazolam.


Fukuta, O., R. L. Braham, et al. (1994). "The sedative effects of intranasal midazolam administration in the dental treatment of patients with mental disabilities. Part 2: optimal concentration of intranasal midazolam." J Clin Pediatr Dent 18(4): 259-65.

            In a previous paper, we reported on the effect of a 0.2 mg/kg dose of midazolam, administered intranasally, prior to performing various restorative dental procedures on a group of mentally disabled patients under local anesthesia and nitrous oxide/oxygen analgesia. The purpose of this study was to compare the clinical and possible adverse effect of doses of 0.2 mg/kg and 0.3 mg/kg midazolam, administered intranasally, and to determine the most appropriate concentration for the drug when administered by this route. Patients were assessed by a behavioral test which consisted of a scale from 1-7 with 3 ranges: markedly effective (1-3), effective (4-5) or ineffective (6-7). Forty- three mentally handicapped patients, aged 5 to 20 years, all of whom had previously exhibited highly combative and resistant behavior toward dental treatment under local anesthesia, were stratified by age and randomly assigned in a double blind manner to two groups, receiving either 0.2 mg/kg or 0.3 mg/kg midazolam administered intranasally. Group 1, consisting of 22 patients, average age 11 years 8 months, received 0.2 mg/kg. Group 2 consisted of 21 patients, average age 13 years 8 months, each of whom was administered 0.3 mg/kg intranasal midazolam. Only patients assessed as ASA anesthesia status I or II were admitted to the study. Subsequent to intranasal administration of midazolam, no patient rejected the nasal mask nor refused to inhale nitrous oxide/oxygen. The induction of nitrous oxide/oxygen sedation and oral examination were effected smoothly in every case in the two groups.(ABSTRACT TRUNCATED AT 250 WORDS)


Gardner-Nix, J. (2001). "Oral transmucosal fentanyl and sufentanil for incident pain." J Pain Symptom Manage 22(2): 627-30.


Good, P., K. Jackson, et al. (2009). "Intranasal sufentanil for cancer-associated breakthrough pain." Palliat Med 23(1): 54-8.

            The objective of this study was to demonstrate the efficacy, safety and patient acceptability of the use of intranasal sufentanil for cancer-associated breakthrough pain. This was a prospective, open label, observational study of patients in three inpatient palliative care units in Australia. Patients on opioids with cancer-associated breakthrough pain and clinical evidence of opioid responsiveness to their breakthrough pain were given intranasal (IN) Sufentanil via a GO Medical patient controlled IN analgesia device. The main outcome measures were pain scores, need to revert to previous breakthrough opioid after 30 min, number of patients who chose to continue using IN sufentanil, and adverse effects. There were 64 episodes of use of IN sufentanil for breakthrough pain in 30 patients. There was a significant reduction in pain scores at 15 (P < 0.0001) and 30 min (P < 0.0001). In only 4/64 (6%) episodes of breakthrough pain did the participants choose to revert to their prestudy breakthrough medication. Twenty-three patients (77%) rated IN sufentanil as better than their prestudy breakthrough medication. The incidence of adverse effects was low and most were mild. Our study showed that IN sufentanil can provide relatively rapid onset, intense but relatively short lasting analgesia and in the palliative care setting it is an effective, practical, and safe option for breakthrough pain.


Harlos, M. (2002). "Palliative Care Incident Pain and Incident Dyspnea Protocol." Internet public domain protocol:

            This is a protocol for transmucosal (sublingual and intranasal) fentanyl and sufentanil to treat pain and dyspnea in hospice setting.


Hollenhorst, J., S. Munte, et al. (2001). "Using intranasal midazolam spray to prevent claustrophobia induced by MR imaging." AJR Am J Roentgenol 176(4): 865-8.

            OBJECTIVE: Up to 37% of patients undergoing MR imaging examinations experience moderate to severe levels of anxiety that necessitate the termination of the procedure in 5-10% of patients. Although the clinical use of MR imaging has increased, effective procedures to handle claustrophobia are lacking. We evaluated the effectiveness of intranasally administered midazolam spray in preventing claustrophobic responses of patients undergoing MR imaging. SUBJECTS AND METHODS: Fifty-four patients scheduled for MR imaging were included in this prospective study. Anxiety and sedation of patients were evaluated before drug administration, immediately before MR imaging, and at the end of the procedure. The Spielberger State-Trait Anxiety Inventory, the visual analogue scale of anxiety, and a five-point sedation scale were used. Half the patients received intranasal spray applications of 4 mg midazolam, whereas the other patients received a placebo, in a randomized, double-blind study design (six sprayings of 0.5% midazolam solution or NaCl 0.9%, respectively). The intensity of the sensation of burning of the nasal mucosa was rated by patients using a three-point scale (no, slight, or strong burning). The quality of scan images was evaluated by a radiologist using a five-point scale (0 = extremely poor, 5 = excellent). RESULTS: No cancellations occurred with patients who received midazolam, whereas four of 27 patients receiving placebo panicked and terminated the scanning procedure. The initial anxiety and sedation scores did not differ between the groups. Patients who received midazolam spray were more sedated and less anxious immediately before entering the MR scanner and reported a more intense slight transient burning of the nasal mucosa than those in the placebo group. The quality of the MR image was higher in the midazolam group. CONCLUSION: A sizeable reduction in MR imaging-related anxiety and improved MR image quality were seen with patients who received intranasal midazolam spray. With the exception of transient burning of the nasal mucosa, no adverse effects were reported. This simple and safe method is useful in sedating patients for MR imaging and other minor procedures.


Holsti, M., B. L. Sill, et al. (2007). "Prehospital intranasal midazolam for the treatment of pediatric seizures." Pediatr Emerg Care 23(3): 148-53.

            BACKGROUND: The local emergency medical services (EMS) council implemented a new pediatric treatment protocol using a Mucosal Atomization Device (MAD) to deliver intranasal (IN) midazolam for seizure activity. METHODS: We sought to compare outcomes in seizing pediatric patients treated with IN midazolam using a MAD (IN-MAD midazolam) to those treated with rectal (PR) diazepam, 18 months before and after the implementation of the protocol. RESULTS: Of 857 seizure patients brought by EMS to our emergency department (ED), 124 patients (14%) had seizure activity in the presence of EMS and were eligible for inclusion in this study. Of the 124 patients eligible for this study, 67 patients (54%) received no medications in the prehospital setting, 39 patients (32%) were treated with IN-MAD midazolam, and 18 patients (15%) were treated with PR diazepam. Median seizure time noted by EMS was 19 minutes longer for PR diazepam (30 minutes) when compared with IN-MAD midazolam (11 minutes, P = 0.003). Patients treated with PR diazepam in the prehospital setting were significantly more likely to have a seizure in the ED (odds ratio [OR], 8.4; confidence interval [CI], 1.6-43.7), ED intubation (OR, 12.2; CI, 2.0-75.4), seizure medications in the ED to treat ongoing seizure activity (OR, 12.1; CI, 2.2-67.8), admission to the hospital (OR, 29.3; CI, 3.0-288.6), and admission to the pediatric intensive care unit (OR, 53.5; CI, 2.7-1046.8). CONCLUSIONS: The IN-MAD midazolam controlled seizures better than PR diazepam in the prehospital setting and resulted in fewer respiratory complications and fewer admissions.


Huge, V., M. Lauchart, et al. (2009). "Effects of low-dose intranasal (S)-ketamine in patients with neuropathic pain." Eur J Pain.


Jackson, K., M. Ashby, et al. (2002). "Pilot dose finding study of intranasal sufentanil for breakthrough and incident cancer-associated pain." J Pain Symptom Manage 23(6): 450-2.


Jackson, K., M. Ashby, et al. (2001). ""Burst" ketamine for refractory cancer pain: an open-label audit of 39 patients." J Pain Symptom Manage 22(4): 834-42.

            The results of a novel approach to the use of ketamine in refractory cancer pain are reported. In this prospective, multicenter, unblinded, open-label audit, 39 patients (with a total of 43 pains) received a short duration (3 to 5 days) ketamine infusion. The initial dose of 100 mg/24 hr was escalated if required to 300 mg/24 hr and then to a maximum dose of 500 mg/24hr. The overall response rate was 29/43 (67%). Analysis of results according to pain mechanisms showed that 15/17 somatic and 14/23 neuropathic pains responded. In 5 patients who appeared to respond, it is possible that another concurrent intervention may have contributed in whole or part for the pain relief observed. After cessation of ketamine, 24/29 maintained good pain control, with a maximum documented duration of eight weeks. However, 5 of the initial 29 responders experienced a recurrence of pain within 24 hours, and ketamine was recommenced. Of these, 2 underwent another intervention for pain control while 3 continued on ketamine until their deaths between two and four weeks later. Twelve patients reported adverse psychomimetic effects, with the incidence rising with increasing dose. Four of these were non-responders and the ketamine was stopped. Eight were responders, and in 3 the adverse effects were rendered acceptable with dose reduction; the other 5 rejected a dose reduction. The results reported suggest the need for further investigation of the place of ketamine in cancer pain management.


Kaufman, E., E. Davidson, et al. (1994). "Comparison between intranasal and intravenous midazolam sedation (with or without patient control) in a dental phobia clinic." J Oral Maxillofac Surg 52(8): 840-3.

            Two new modes of sedation; patient-controlled sedation (PCS) and intranasal sedation (INS) were compared with the traditional bolus intravenous sedation (BIVS) while delivering dental care to apprehensive patients in a specialized dental fear clinic. Effective sedation was evaluated in a randomized, prospective study in 42 ASA 1 and 2 patients, in a factorial design. Eighteen patients were sedated with .5% midazolam INS. Ten patients received intravenous PCS via a patient-controlled analgesia pump containing midazolam, and 14 patients received intermittent intravenous boluses of 1 mg midazolam given as needed (BIVS). Appropriate local anesthetic nerve blocks with 2% lidocaine with 1:100,000 epinephrine, and supplementary inhalation of nitrous oxide and oxygen via a nasal mask, were also given to all patients in the study. The dosage requirement with PCS was higher than that found with INS or BIVS. However, PCS produced some anxiety reduction when compared with INS and BIVS. It also reduced interfering movements during treatment more effectively than the other sedation modes. No complications were detected in any of the patients and they were able to leave the clinic within 1 hour after completion of treatment.


Kendall, J. M., B. C. Reeves, et al. (2001). "Multicentre randomised controlled trial of nasal diamorphine for analgesia in children and teenagers with clinical fractures." Bmj 322(7281): 261-5.

            OBJECTIVE: To compare the effectiveness of nasal diamorphine spray with intramuscular morphine for analgesia in children and teenagers with acute pain due to a clinical fracture, and to describe the safety profile of the spray. DESIGN: Multicentre randomised controlled trial. SETTING: Emergency departments in eight UK hospitals. PARTICIPANTS: Patients aged between 3 and 16 years presenting with a clinical fracture of an upper or lower limb. MAIN OUTCOME MEASURES: Patients' reported pain using the Wong Baker face pain scale, ratings of reaction to treatment of the patients and acceptability of treatment by staff and parents, and adverse events. RESULTS: 404 eligible patients completed the trial (204 patients given nasal diamorphine spray and 200 given intramuscular morphine). Onset of pain relief was faster in the spray group than in the intramuscular group, with lower pain scores in the spray group at 5, 10, and 20 minutes after treatment but no difference between the groups after 30 minutes. 80% of patients given the spray showed no obvious discomfort compared with 9% given intramuscular morphine (difference 71%, 95% confidence interval 65% to 78%). Treatment administration was judged acceptable by staff and parents, respectively, for 98% (199 of 203) and 97% (186 of 192) of patients in the spray group compared with 32% (64 of 199) and 72% (142 of 197) in the intramuscular group. No serious adverse events occurred in the spray group, and the frequencies of all adverse events were similar in both groups (spray 24.1% v intramuscular morphine 18.5%; difference 5.6%, -2.3% to 13.6%). CONCLUSION: Nasal diamorphine spray should be the preferred method of pain relief in children and teenagers presenting to emergency departments in acute pain with clinical fractures. The diamorphine spray should be used in place of intramuscular morphine.


Knox, D. J., B. J. McLeod, et al. (1995). "Acute phantom limb pain controlled by ketamine." Anaesth Intensive Care 23(5): 620-2.


Kress, H. G., A. Oronska, et al. (2009). "Efficacy and tolerability of intranasal fentanyl spray 50 to 200 microg for breakthrough pain in patients with cancer: a phase III, multinational, randomized, double-blind, placebo-controlled, crossover trial with a 10-month, open-label extension treatment period." Clin Ther 31(6): 1177-91.

            OBJECTIVE: This trial investigated the efficacy and long-term tolerability of intranasal fentanyl spray (INFS) 50 to 200 microg in the treatment of breakthrough pain in opioid-tolerant patients with cancer. METHODS: This Phase III, double-blind, randomized, placebo-controlled, crossover trial was conducted at pain centers, anesthesiology departments, palliative care units, and oncology clinics in Austria, Denmark, France, Germany, and Poland. Eligible patients were adults with cancer receiving a stable dose of long-term opioid treatment for the control of background pain. Patients were treated at home with their effective dose of INFS (50, 100, or 200 microg) or inactive spray (placebo) in a randomized sequence for 3 weeks, followed by a 10-month, open-label tolerability phase during which they received their effective dose of INFS. Throughout the study, patients were allowed to use their usual rescue medication, which was recorded in patient diaries. The primary efficacy end point was the pain intensity difference at 10 minutes after study drug administration (PID(10)), as assessed using an 11-point numeric rating scale (0 = no pain to 10 = worst pain imaginable). An effect size of 0.5 for PID was considered clinically relevant. The rate of response, defined as PID(10) >2, was also assessed. Adverse events (AEs) were recorded in patient diaries during the efficacy period and reported in monthly clinic visits and follow-up weekly telephone contacts during the extension period. RESULTS: In all, 120 patients were enrolled and achieved an effective dose; 113 were randomized and 111 were included in the intent-to-treat analysis set (56 men, 55 women; mean [SD] age, 60.6 [9.45] years; mean weight, 70.3 kg [men] and 65.3 kg [women]; white race, 107 [96.4%]; INFS 50 microg, 18; INFS 100 microg, 48; INFS 200 microg, 45; placebo, 110). PID(10) with INFS was 2-fold that with placebo (adjusted means, 2.36 vs 1.10; adjusted difference, 1.26 [greater than the clinically relevant difference of 0.5]; P < 0.001). Additional analysis revealed that the mean response rate with all 3 doses of INFS was 51.1% versus 20.9% with placebo. The prevalence of AEs was 22/111 (19.8%) during the efficacy period, during which the most frequently reported AEs were nausea (5 [4.5%]) and vertigo (2 [1.8%]). No serious AEs were considered related to the study drugs. In all, 108 patients entered the extension period, with a mean duration of exposure to INFS of 134.9 days. Progression of underlying malignant disease was the most common AE reported during this period (55 [50.9%]); this event was not considered treatment related. CONCLUSIONS: In these opioid-tolerant patients with cancer, INFS at doses of 50, 100, and 200 microg was associated with an onset of activity at 10 minutes and effective treatment of breakthrough pain compared with placebo. All doses were generally well tolerated and clinically efficacious.


Kulbe, J. (1998). "The use of ketamine nasal spray for short-term analgesia." Home Healthc Nurse 16(6): 367-70.


Lahat, E., M. Goldman, et al. (2000). "Comparison of intranasal midazolam with intravenous diazepam for treating febrile seizures in children: prospective randomised study." Bmj 321(7253): 83-6.

            Objective: To compare the safety and efficacy of midazolam given intranasally with diazepam given intravenously in the treatment of children with prolonged febrile seizures. Design: Prospective randomised study. Setting: Paediatric emergency department in a general hospital. Subjects: 47 children aged six months to five years with prolonged febrile seizure (at least 10 minutes) during a 12 month period. Interventions: Intranasal midazolam (0.2 mg/kg) and intravenous diazepam (0.3 mg/kg). Main outcome measures: Time from arrival at hospital to starting treatment and cessation of seizures. Results: Intranasal midazolam and intravenous diazepam were equally effective. Overall, 23 of 26 seizures were controlled with midazolam and 24 out of 26 with diazepam. The mean time from arrival at hospital to starting treatment was significantly shorter in the midazolam group (3.5 (SD 1.8) minutes, 95% confidence interval 3.3 to 3.7) than the diazepam group (5.5 (2.0), 5.3 to 5.7). The mean time to control of seizures was significantly sooner (6.1 (3.6), 6.3 to 6.7) in the midazolam group than the diazepam group (8.0 (0.5), 7. 9 to 8.3). No significant side effects were observed in either group. Conclusion: Seizures were controlled more quickly with intravenous diazepam than with intranasal midazolam, although midazolam was as safe and effective as diazepam. The overall time to cessation of seizures after arrival at hospital was faster with intranasal midazolam than with intravenous diazepam. The intranasal route can possibly be used not only in medical centres but in general practice and, with appropriate instructions, by families of children with recurrent febrile seizures at home.


Lane, R. D. and J. E. Schunk (2008). "Atomized intranasal midazolam use for minor procedures in the pediatric emergency department." Pediatr Emerg Care 24(5): 300-3.

            BACKGROUND: Procedural sedation is increasingly more common in pediatric emergency departments. We report our experience with intranasal midazolam (INM) using a unique atomization delivery device, specifically the efficacy and safety of this method of sedation. METHODS: We performed a retrospective chart review of children who received INM sedation in the emergency department from April 1, 2005, through June 30, 2005. All children aged 1 to 60 months who received INM as the initial means of sedation were eligible for the study. Patients were excluded if they were older than 60 months. RESULTS: There were 205 patients who received INM for sedation and who met the study criteria. The mean age was 31.3 +/- 13.2 months (range, 1.5-60 months). The mean and median initial INM dose was 0.4 mg/kg (range, 0.3-0.8 mg/kg). Laceration repair was the most common procedure necessitating sedation (89%). The median degree-of-sedation score achieved was 2.0 (anxiolysis). Eleven patients (5.4%; 95% CI, 3%-9%) required an additional sedative to complete the procedure. Ten of the 11 patients received ketamine as the adjunctive sedative, and 1 patient required additional INM. The average time of last oral intake to start of sedation was 3.5 hours (range, 0.5-10.0 hours). Thirty six patients (18%) were NPO for 2 hours or less. There was 1 adverse event (0.5%; 95% CI, 0%-3%). This was a minor desaturation episode following ketamine administration requiring brief blow by oxygen. There were no adverse events (0%; 95% CI, 0%-2%) in patients who received INM alone. CONCLUSION: We conclude that atomized INM is effective in providing anxiolysis to children undergoing minor procedures in the pediatric emergency department. We are encouraged that no adverse events occurred with the use of INM alone despite relatively short fasting times.


Lazol, J. P. and C. G. DeGroff (2009). "Minimal sedation second dose strategy with intranasal midazolam in an outpatient pediatric echocardiographic setting." J Am Soc Echocardiogr 22(4): 383-7.

            BACKGROUND: Anxiety and movement in children during transthoracic echocardiography (TTE) can compromise study quality and reliability. Minimal sedation is often required. Intranasal midazolam (INM), used in various procedures, is an excellent sedative. Optimal INM dosing strategies for uncooperative children undergoing TTE are largely unknown, including second-dose INM strategies, introduced to maximize the potential for successful sedation and minimize risk. The purpose of this retrospective review was to evaluate the effectiveness of a second-dose INM minimal sedation strategy recently adopted at the Children's Hospital of Pittsburgh. METHODS: The strategy incorporates a second dose of INM if needed (10-15 minutes after the first dose) to obtain the desired level of anxiolysis. The effectiveness of this strategy was assessed in 100 consecutive patients (age range, 1-59 months). RESULTS: There were no reported complications, minimal untoward side reactions, and no delays in discharge. Eighty patients attained satisfactory minimal sedation levels. CONCLUSION: A second-dose INM strategy was effective in achieving satisfactory minimal sedation in children undergoing TTE. The results of this study also suggest that only a small proportion of patients would benefit from a one-dose INM strategy.


Malinovsky, J. M., C. Populaire, et al. (1995). "Premedication with midazolam in children. Effect of intranasal, rectal and oral routes on plasma midazolam concentrations." Anaesthesia 50(4): 351-4.

            We report a study performed to compare the time and plasma drug concentrations necessary to achieve a similar state of sedation after midazolam premedication given by various routes in children of 2-5 years old. Children were randomly allocated to one of three groups to receive midazolam 0.2 given intranasally, 0.5 given orally or 0.3 given rectally. Sedation was measured regularly until venepuncture was possible in a cooperative child. At this time, a first blood sample was taken to measure plasma concentration, followed by another 10 min later. Anaesthesia consisted of intravenous propofol supplemented with regional analgesia. At recovery from anaesthesia, a third blood sample was taken. Adequate sedation occurred sooner (7.7, SD 2.4 min) with intranasal than oral (12.5, SD 4.9 min) or rectal (16.3, SD 4.2 min) midazolam. The initial blood levels were lower when the drug was given by the alimentary routes despite higher doses (146, SD 51 in 11.5, SD 3.9 min; 104, SD 34 in 21 +/- 6 min; and 93, SD 63 in 23.1, SD 3.5 min for the intra nasal, rectal and oral routes respectively). Duration of surgical procedures, and of propofol infusion, and recovery from anaesthesia was similar for the three groups. The only problem arose in a 30-month-old boy in the intranasal group who developed respiratory depression with a plasma midazolam concentration of 169 Intranasal midazolam is an excellent alternative for rapid premedication provided that respiratory monitoring is used.


Manley, M. C., N. J. Ransford, et al. (2008). "Retrospective audit of the efficacy and safety of the combined intranasal/intravenous midazolam sedation technique for the dental treatment of adults with learning disability." Br Dent J.

            Introduction The provision of dental care for adults with severe learning disability presents problems. The approach to treatment has often been provided under general anaesthesia tending to result in exodontia rather than restorative care. This paper presents an alternative to this option using conscious sedation.Methods A multi-centred retrospective audit was reported on using data from Canterbury, Warwick, Dorset and Cardiff. Patients included adults with varying degrees of disability for whom treatment using local anaesthesia, inhalation sedation, and the acceptance of intravenous cannulation was not possible. Sedation was provided by midazolam first administered by the intranasal followed by the intravenous route.Results From a total of 222 episodes of sedation 128 (57.65%) accepted treatment well and 75 (33.78%) presented slight problems which did not compromise treatment. In 19 cases (8.55%) treatment with sedation was not possible and a referral was made for general anaesthesia.Conclusions Results showed that a range of different treatments were carried out including advanced restorative care. This paper proposes that the technique described is safe and effective in providing a good standard of dental care for adults with severe learning disability.


Mercadante, S., E. Arcuri, et al. (2000). "Analgesic effect of intravenous ketamine in cancer patients on morphine therapy: a randomized, controlled, double-blind, crossover, double-dose study." J Pain Symptom Manage 20(4): 246-52.

            Pain not responsive to morphine is often problematic. Animal and clinical studies have suggested that N-methyl-D-aspartate (NMDA) antagonists, such as ketamine, may be effective in improving opioid analgesia in difficult pain syndromes, such as neuropathic pain. A slow bolus of subhypnotic doses of ketamine (0.25 mg/kg or 0.50 mg/kg) was given to 10 cancer patients whose pain was unrelieved by morphine in a randomized, double-blind, crossover, double-dose study. Pain intensity on a 0 to 10 numerical scale; nausea and vomiting, drowsiness, confusion, and dry mouth, using a scale from 0 to 3 (not at all, slight, a lot, awful); Mini-Mental State Examination (MMSE) (0-30); and arterial pressure were recorded before administration of drugs (T0) and after 30 minutes (T30), 60 minutes (T60), 120 minutes (T120), and 180 minutes (T180). Ketamine, but not saline solution, significantly reduced the pain intensity in almost all the patients at both doses. This effect was more relevant in patients treated with higher doses. Hallucinations occurred in 4 patients, and an unpleasant sensation ("empty head") was also reported by 2 patients. These episodes reversed after the administration of diazepam 1 mg intravenously. Significant increases in drowsiness were reported in patients treated with ketamine in both groups and were more marked with ketamine 0.50 mg/kg. A significant difference in MMSE was observed at T30 in patients who received 0.50 mg/kg of ketamine. Ketamine can improve morphine analgesia in difficult pain syndromes, such as neuropathic pain. However, the occurrence of central adverse effects should be taken into account, especially when using higher doses. This observation should be tested in studies of prolonged ketamine administration.


Mercadante, S., G. Porzio, et al. (2008). "Sustained-release oral morphine versus transdermal fentanyl and oral methadone in cancer pain management." Eur J Pain 12(8): 1040-6.

            PURPOSE: The aim of this study was to compare the analgesic and adverse effects, doses, as well as cost of opioid drugs, supportive drug therapy and other analgesic drugs in patients treated with oral sustained-release morphine, transdermal fentanyl, and oral methadone. PATIENTS AND METHODS: One hundred and eight cancer patients, no longer responsive to opioids for moderate pain, were selected to randomly receive initial daily doses of 60 mg of oral sustained-release morphine, 15 mg of oral methadone, or 0.6 mg (25 microg/h) of transdermal fentanyl. Oral morphine was used as breakthrough pain medication during opioid titration. Opioid doses, pain intensity, adverse effects, symptomatic drugs, were recorded at week intervals for 4 weeks. Costs of opioid therapy, supportive drugs, and other analgesic drugs were also evaluated. RESULTS: Seventy patients completed the 4 weeks period of study. Five, five, and four patients, treated with oral morphine, transdermal fentanyl, and oral methadone, respectively, required opioid switching. No differences in pain and symptom intensity were observed. Opioid escalation index was significantly lower in patients receiving methadone (p<0.0001), although requiring up and down changes in doses. At the doses used, methadone was significantly less expensive (p<0.0001), while the use and costs of supportive drugs and other analgesics were similar in the three groups. No relevant differences in adverse effects were observed among the groups during either the titration phase and chronic treatment. CONCLUSION: All the three opioids used as first-line therapy were effective, well tolerated, and required similar amounts of symptomatic drugs or co-analgesics. Methadone was significantly less expensive, but required more changes, up and down, of the doses, suggesting that dose titration of this drug requires major clinical expertise.


Mercadante, S., L. Radbruch, et al. (2009). "A comparison of intranasal fentanyl spray with oral transmucosal fentanyl citrate for the treatment of breakthrough cancer pain: an open-label, randomised, crossover trial." Curr Med Res Opin 25(11): 2805-15.

            OBJECTIVE: The efficacy of intranasal fentanyl spray (INFS) was compared with that of oral transmucosal fentanyl citrate (OTFC) for the relief of cancer-related breakthrough pain (BTP) in an open-label, crossover trial. METHODS: Adult cancer patients receiving stable background opioid treatment and experiencing BTP episodes were recruited from 44 study centres in seven European countries (Austria, France, Germany, Italy, Poland, Spain and the United Kingdom); of the 196 patients enrolled, 139 were randomised to receive INFS followed by OTFC, or vice versa. Patients were titrated to an effective dose of one agent (50, 100 or 200 microg INFS; 200, 400, 600, 800, 1200 or 1600 microg OTFC) to treat six BTP episodes, then titration and treatment were repeated with the other agent. The primary outcome was patient-recorded time to onset of 'meaningful' pain relief. Secondary outcomes included pain intensity difference (PID) at 10 and 30 minutes (PID(10), PID(30)), sum of PID at 15 and 60 minutes (SPID(0-15), SPID(0-60)), ease of administration, treatment preference and relationship between background opioid dose and effective INFS dose. Additional outcome measures included proportions of episodes with > or =33% and > or =50% pain intensity (PI) reduction, and PID at additional time points. Clinical trial registration number: NCT00496392. RESULTS: Among the intention-to-treat population (n = 139), median time to onset of 'meaningful' pain relief was 11 minutes with INFS versus 16 minutes with OTFC; 65.7% of patients attained faster time to 'meaningful' pain-relief onset with INFS (p < 0.001). PID was statistically significantly greater for INFS than OTFC from 5 minutes post-dosing. Significantly more INFS-treated breakthrough pain episodes achieved clinically important pain relief (> or =33% and > or =50% PI reduction) up to 30 minutes post-dosing. The proportions of episodes treated with INFS and OTFC achieving a PI reduction of > or =33% at 5 minutes were 25.3% versus 6.8% (p < 0.001), and at 10 minutes were 51.0% versus 23.6% (p < 0.001), respectively; the proportions of episodes treated with INFS and OTFC achieving a > or =50% PI reduction at 5 minutes were 12.8% versus 2.1% (p < 0.001), and at 10 minutes were 36.9% versus 9.7% (p < 0.001), respectively. Higher SPID(0-15) and SPID(0-60) scores were achieved with INFS (p < 0.001). More patients preferred INFS than OTFC (p < 0.001) and more patients found it very easy/easy to use. Both treatments were well tolerated. In the safety population (n = 139), 56.8% (n = 79) of patients experienced > or =1 AE during the trial. The only AE that occurred in > or =5% of patients in either treatment group was nausea. Among those patients who experienced serious AEs (13.7%, n = 19), none were considered to be related to either study medication. There was a weak correlation between effective INFS doses and background opioid doses. CONCLUSION: In this open-label, randomised, crossover trial, significantly more patients attained faster 'meaningful' pain relief with INFS than OTFC, and more patients preferred INFS to OTFC.


Mercadante, S., P. Villari, et al. (2007). "Transmucosal fentanyl vs intravenous morphine in doses proportional to basal opioid regimen for episodic-breakthrough pain." Br J Cancer 96(12): 1828-33.

            The use of supplemental doses of opioids is commonly suggested to manage breakthrough pain. A comparative study of intravenous morphine (IV-MO) and oral transmucosal fentanyl citrate (OTFC) given in doses proportional to the basal opioid regimen was performed in 25 cancer patients receiving stable opioid doses. For each episode, when it occurred and 15 and 30 min after the treatment, pain intensity and opioid-related symptoms were recorded. Fifty-three couples of breakthrough events, each treated with IV-MO and OTFC, were recorded. In episodes treated with IV-MO, pain intensity decreased from a mean of 6.9 to 3.3 and to 1.7 at T1 and T2, respectively. In episodes treated with OTFC, pain intensity decreased from a mean of 6.9 to 4.1 and to 2.4 at T1 and T2, respectively. Statistical differences between the two treatments were found at T1 (P=0.013), but not at T2 (P=0.059). Adverse effects were comparable and were not significantly related with the IV-MO and OTFC doses. Intravenous morphine and OTFC in doses proportional to the scheduled daily dose of opioids were both safe and effective, IV-MO having a shorter onset than OTFC. Future comparative studies with appropriate design should compare titration methods and proportional methods of OTFC dosing.


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): 875-82.


Osborn, H. and M. Jefferson (2009). "Intranasal alfentanil for severe intractable angina in inoperable coronary artery disease." Palliat Med.

            Chronic refractory angina can lead to multiple acute hospital admissions. This can be due to patient and healthcare professional misconceptions regarding the meaning of the chest pain experienced. Symptom control, psychological support and education form an important part of the management of this condition. We describe a case study where intranasal alfentanil provided rapid relief of symptoms preventing repeated hospital admissions.


Portenoy, R. K., J. Messina, et al. (2007). "Fentanyl buccal tablet (FBT) for relief of breakthrough pain in opioid-treated patients with chronic low back pain: a randomized, placebo-controlled study." Curr Med Res Opin 23(1): 223-33.

            BACKGROUND: Short-acting opioids are commonly used to treat breakthrough pain (BTP) and rapid-onset formulations are being developed to improve the effectiveness of this approach. Fentanyl buccal tablet (FBT) is a new formulation of fentanyl that enhances transbuccal drug delivery via an effervescent reaction and may provide relatively rapid-onset analgesia. FBT was evaluated for BTP in opioid-treated patients with chronic low back pain--the first such study in a population with chronic non-cancer pain. DESIGN: Randomized, double-blind, placebo-controlled. Patients and setting: Patients with chronic low back pain receiving long-term opioid therapy at 16 pain treatment centers in the United States. PROCEDURES: Following open-label titration to identify an effective FBT dose, patients were randomly assigned to one of three double-blind dose sequences (six doses of FBT, three placebo) to treat nine BTP episodes. Pain intensity (PI), measured on an 11-point scale (0 = no pain; 10 = worst pain), and other outcomes were assessed for 2 h after dosing. DATA ANALYSIS: The primary efficacy measure was the sum of pain intensity differences (PIDs) for the first 60 min (SPID60); secondary efficacy measures included PIDs at other time points, pain relief (PR), meaningful PR, time to meaningful PR, use of supplementary BTP medication, and self/investigator-reported adverse events. RESULTS: Of the 124 patients screened, 105 patients were enrolled, 84 identified an effective FBT dose, and 77 entered the double-blind phase. SPID60 significantly favored FBT (p < 0.0001). All secondary measures also favored FBT, with PIDs and PR showing significant differences versus placebo as early as 10 and 15 min, respectively. An improvement in PI score of > or = 33% occurred in a significantly larger proportion of FBT-treated episodes versus placebo from 15 min (20% vs. 11%, p < 0.01) through 2 h (65% vs. 28%, p < 0.0001). Patients were approximately four times more likely to require supplemental opioids for BTP episodes following administration of placebo compared with episodes treated with FBT. AEs were typical for opioids, and were mostly reported during dose titration. Limitations of this study may be related to its open-label dose-titration phase (which has the potential to compromise blinding) and the recruitment of patients from pain clinics, which could potentially yield a study population that is not representative of the general population with BTP. CONCLUSIONS: FBT was efficacious and well tolerated in the treatment of BTP in opioid-treated patients with chronic low back pain.


Portenoy, R. K., D. Taylor, et al. (2006). "A randomized, placebo-controlled study of fentanyl buccal tablet for breakthrough pain in opioid-treated patients with cancer." Clin J Pain 22(9): 805-11.

            OBJECTIVES: Cancer-related breakthrough pain (BTP) is typically managed with a short-acting oral opioid, taken as needed during a fixed-schedule opioid regimen. The conventional approach may not provide the onset of analgesia required for BTP for many patients, because the onset of analgesia with short-acting opioids lags behind the time course of the majority of episodes of BTP. The fentanyl buccal tablet (FBT) employs a novel delivery system that enhances the rate and extent of absorption of fentanyl through the buccal mucosa. This double-blind, randomized, placebo-controlled study evaluated the efficacy, safety, and tolerability of FBT in opioid-treated patients with cancer-related BTP. METHODS: After an open-label titration (N=123) to identify an effective FBT dose to treat BTP episodes, 77 patients were randomly assigned to 1 of 18 prespecified dose sequences of 10 tablets (7 FBT and 3 placebo). Pain intensity, pain relief (PR), and global performance of the medication were recorded at regular time intervals between 15 and 60 minutes. Pain intensity differences (PID), the summed PID (SPID), and summed total PR were calculated. The SPID at 30 minutes (SPID30) was the primary efficacy variable. Adverse events were reported. RESULTS: Sixty-five percent (80/123) of patients were titrated to an effective dose. The mean (SE) SPID30 for FBT was 3.0+/-0.12 versus 1.8+/-0.18 for placebo (P<0.0001). Measures of PR, PID, SPID, summed total PR, and patient ratings of global performance of medication significantly favored FBT over placebo at all time points. Adverse events were typical of opioid drugs. Poor oral tolerability was noted in 2 patients. CONCLUSIONS: FBT is efficacious and safe in the treatment of cancer-related BTP.


Rauck, R. L., M. Tark, et al. (2009). "Efficacy and long-term tolerability of sublingual fentanyl orally disintegrating tablet in the treatment of breakthrough cancer pain." Curr Med Res Opin.

            Abstract Background and objectives: Breakthrough cancer pain (BTcP) represents an important clinical challenge in the care of patients with cancer. This trial evaluated the efficacy and long-term tolerability of a sublingual formulation of the fast-acting opioid fentanyl, for the treatment of BTcP in opioid-tolerant patients with cancer. Research design and methods: This was a randomized, placebo-controlled, multi-center, phase III trial, conducted in opioid-tolerant male and female patients (aged >/=17 years) with BTcP. The study was conducted at 36 centers across the USA. The study comprised a 2-week open-label titration phase, followed by a double-blind efficacy phase, during which patients received sublingual fentanyl citrate orally disintegrating tablet (sublingual fentanyl ODT) or placebo, in a random order. The primary efficacy endpoint was the sum of pain intensity difference (SPID) over 30 min post-administration. Secondary efficacy endpoints included pain intensity difference (PID) and pain relief (PR) throughout the 60-min post-dose assessment period. Following efficacy evaluation, patients entered a long-term safety phase of up to 12 months. Adverse events were recorded throughout the study. [Clinical trial registration: NCT00262678] Results: A total of 131 patients entered the titration phase, of whom 61 were included in the primary efficacy analysis. Sublingual fentanyl ODT provided significant improvements in SPID relative to placebo at 30 min (49.5 vs. 36.6, p = 0.0004) and 60 min post-administration (143.0 vs. 104.5, p = 0.0002). Furthermore, sublingual fentanyl ODT provided significant improvements in PID and PR compared to placebo, from 10 min post-dose (p = 0.0055 and p = 0.049 for PID and PR, respectively). Patient recruitment was stopped early, due to positive interim analysis results (significant at prespecified level, p </= 0.0414). Overall, sublingual fentanyl ODT was well-tolerated both systemically and sublingually, with 41 patients experiencing >/=1 study drug-related adverse event (AE). The most common AEs included nausea (12.2%), vomiting (5.3%) and somnolence (4.6%). One serious AE (mild affect lability) was considered possibly related to study medication. The observed pattern of AEs was consistent with that previously observed with fentanyl. Conclusions: Sublingual fentanyl ODT was efficacious and well-tolerated for the treatment of BTcP in opioid-tolerant patients with cancer. Sublingual fentanyl ODT provided significant improvements in pain intensity compared to placebo, from 10 min post-administration and throughout the 60-min post-dose assessment period. Sublingual fentanyl ODT was well tolerated over 12 months of treatment.


Schwagmeier, R., N. Boerger, et al. (1995). "Pharmacokinetics of intranasal alfentanil." J Clin Anesth 7(2): 109-13.

            STUDY OBJECTIVE: To determine the pharmacokinetics of intranasal and intravenous (IV) administrations of alfentanil in 10 healthy volunteers. DESIGN: Randomized, prospective, double-blind, placebo-controlled, cross-over trial with at least one week between the two modes of administration. SETTING: Healthy volunteers at a university medical center. SUBJECTS: 10 healthy, nondrug-dependent volunteers. INTERVENTIONS: Alfentanil 0.54 mg was administered either intranasally [with 12 ml of sodium chloride (NaCl) 0.9% IV] or IV (with 12 sprays of NaCl 0.9% intranasally). Each subject was assigned once to the intranasal and once to the IV group. To guarantee a complete elimination of alfentanil, there was a time period of at least one week between the different modes of administration. MEASUREMENTS AND MAIN RESULTS: Venous blood was sampled from a cubital vein at 3, 6, 9, 12, 15, 20, 30, 60, and 120 minutes after administration. Alfentanil plasma concentrations were determined by radioimmunoassay. Maximal plasma concentrations were 20.1 ng/ml +/- 7.3 ng/ml after 9 minutes in the intranasal group. At this measurement point, the intranasal alfentanil concentrations were 64.7% (18.7 ng/ml +/- 6.8 ng/ml) of the IV concentrations (28.9 ng/ml +/- 7.9 ng/ml). The calculated bioavailability after intranasal administration was 64.96% +/- 26.3%. CONCLUSIONS: This pharmacokinetic study demonstrates a rapid rise in plasma concentrations, as well as a high bioavailability, following the intranasal administration of alfentanil.


Sitte, T. and C. Bausewein (2008). "Intranasal fentanyl for episodic breathlessness." J Pain Symptom Manage 36(6): e3-6.


Slatkin, N. E., F. Xie, et al. (2007). "Fentanyl buccal tablet for relief of breakthrough pain in opioid-tolerant patients with cancer-related chronic pain." J Support Oncol 5(7): 327-34.

            Fentanyl buccal tablet (FBT) is a new opioid formulation providing rapid-onset analgesia for the treatment of breakthrough pain (BTP). This study evaluated FBT for BTP in opioid-tolerant patients with chronic cancer pain. The study had a randomized, double-blind, placebo-controlled design and was conducted at 30 outpatient treatment centers in the United States. Following open-label titration, patients were randomly assigned to 1 of 18 double-blind dose sequences (7 FBT tablets, 3 placebo) to treat 10 BTP episodes. Pain intensity was measured on an 11-point scale (0 = no pain; 10 = worst pain). The primary efficacy measure was the sum of pain intensity differences (PIDs) for the first 60 minutes (SPID60); secondary efficacy measures included PIDs and pain relief (PR) measured from 5 minutes through 2 hours. Adverse events (AEs) were recorded. Of 129 patients enrolled, 87 entered the double-blind phase. SPID60 significantly favored FBT versus placebo (mean +/- SE, 9.7 +/- 0.63 vs 4.9 +/- 0.50; P < 0.0001). Secondary measures also favored FBT: PIDs and PR showed significant differences versus placebo at 10 minutes (0.9 vs 0.5; 0.815 vs 0.606, respectively, P < 0.0001) and all subsequent time points (P < 0.0001). AEs were typical of opioids (eg, nausea, dizziness, fatigue). In conclusion, in this study of opioid-tolerant patients with chronic cancer pain and BTP, FBT was efficacious, well tolerated, demonstrated rapid onset of analgesia (within 10 minutes), and had a sustained effect.


Stanley, T. H. (2000). "Anesthesia for the 21st Century." BUMC Proceedings 13: 7-10.


Stoker, D. G., K. R. Reber, et al. (2008). "Analgesic efficacy and safety of morphine-chitosan nasal solution in patients with moderate to severe pain following orthopedic surgery." Pain Med 9(1): 3-12.

            Introduction. Parenteral opioids are the standard of care for treating moderate to severe postsurgical pain. This randomized, double-blind, dose-ranging study compared the safety and efficacy of intranasal (IN) morphine with intravenous (IV) morphine and placebo. Methods. In total, 187 postbunionectomy patients with moderate to severe pain were randomized to receive IN morphine 3.75 mg, 7.5 mg, 15 mg, or 30 mg, IV morphine 7.5 mg, or placebo in the single-dose phase and IN morphine 7.5 mg or 15 mg thereafter. The primary outcome was a dose-response assessment for total pain relief based upon visual analog scales. Secondary endpoints included pain intensity, pain relief, patient global evaluation, and time to rescue medication. Safety assessments included adverse events and nasal examination. Results. A statistically significant linear dose response was observed over the IN morphine dose range for 4-hour total pain relief. Patients reported statistically significant pain relief and pain intensity differences following IV morphine and IN morphine at doses of 7.5 mg and greater within 30 minutes postdose, compared with placebo. Median times to rescue medication were 124 and 140 minutes for IN morphine 7.5 mg and 15 mg dosage groups, respectively, and 130 minutes for IV morphine. Local adverse events associated with IN morphine were transient and mostly mild (bad taste, nasal congestion, throat irritation, and sneezing). Systemic adverse events, regardless of route of administration, were dose-related and consistent with expected opioid effects. Conclusions. By multiple measures of pain intensity and pain relief, IN morphine provides sustained analgesia in postsurgical patients and thus may offer a safe and less invasive alternative to IV morphine.


Talon, M. D., L. C. Woodson, et al. (2009). "Intranasal Dexmedetomidine Premedication is Comparable With Midazolam in Burn Children Undergoing Reconstructive Surgery." J Burn Care Res 30(4): 599-605.

            Preoperative anxiety and emergence delirium in children continue to be common even with midazolam premedication. Midazolam is unpleasant tasting even with a flavored vehicle and as a result, patient acceptance is sometimes poor. As an alternative, we evaluated dexmedetomidine administered intranasally. Dexmedetomidine an alpha-2 adrenergic agonist is tasteless, odorless, and painless when administered by this route. Alpha-2 adrenergic agonists produce sedation, facilitate parental separation, and improve conditions for induction of general anesthesia, while preserving airway reflexes. Institutional review board approval was obtained to study 100 pediatric patients randomized to intranasal dexmedetomidine (2 mug/kg) or oral midazolam (0.5 mg/kg) administered 30 to 45 minutes before the surgery. Subjects received general anesthesia with oxygen, nitrous oxide, isoflurane, and analgesics (0.05-0.1 mg/kg morphine or 0.1 mg/kg methadone). Nurses and anesthetists were blinded to the drug administered and evaluated patients for preoperative sedation, conditions for induction of general anesthesia, emergence from anesthesia, and postoperative pain. Responses of 100 patients (50 dexmedetomidine and 50 midazolam) were analyzed. Dexmedetomidine (P = .003) was more effective than midazolam at inducing sleep preoperatively. Dexmedetomidine and midazolam were comparable for conditions at induction (P > 0.05), emergence from anesthesia (P > 0.05), or postoperative pain (P > 0.05). Both drugs were equieffective in these regards. In pediatric patients, dexmedetomidine 2 mug/kg administered intranasally and midazolam 0.5 mg/kg administered orally produced similar conditions during induction and emergence of anesthesia. Intranasal administration of dexmedetomidine is more effective at inducing sleep and in some circumstances offers a useful alternative to oral midazolam in children.


Taylor, D.R., Fisher A.N., Smith A. (2009). Pharmacokinetic and local tolerability profiles of three potential fentanyl nasal spray formulations developed for breakthrough cancer pain compared with oral transmucosal fentanyl citrate. J Clinical Oncology 27 (15S) Abstract

Background: The nasal route offers the ability to enhance fentanyl delivery and better match the rapid onset and short duration (30–60 min) of breakthrough cancer pain compared with standard oral delivery. However, conventional nasal fentanyl solutions can be associated with variable, and sometimes supratherapeutic maximum plasma concentrations (Cmax). To optimise rapid absorption and delivery, three novel nasal spray formulations have been developed: fentanyl pectin nasal spray (FPNS), fentanyl chitosan nasal spray (FChNS), and fentanyl in chitosan-poloxamer 188 solute (FChP). Methods: This phase I, open-label, crossover study was conducted in 18 healthy adult volunteers to compare the pharmacokinetic profiles of the three new nasal fentanyl formulations with oral transmucosal fentanyl citrate (OTFC). Subjects were dosed on four occasions, separated by a >3-day washout period, under naltrexone blockade, with the nasal sprays (each containing fentanyl citrate 100µg in 100µL) and OTFC 200µg according to a randomized sequence. Venous plasma fentanyl concentrations were measured before and up to 24 hours post-dose. Local nasal tolerability was assessed by a clinician and a reactogenicity questionnaire. Results: Compared with OTFC, mean AUCs for all three nasal sprays were significantly higher (P<0.05) and bioavailability significantly greater (FPNS 132%; FChNS 154%, FChP 122%). Median tmax (FPNS 19.8min; FChNS 10.2min, FChP 15.6min) were significantly (P<0.001) reduced (OTFC 90min) and mean Cmax significantly increased with all nasal sprays compared with OTFC. Of the three nasal sprays, FPNS had the lowest nasal reactogenicity symptom incidence. Conclusions: Compared with OTFC, all three fentanyl nasal spray formulations demonstrated enhanced pharmacokinetic profiles appropriate for breakthrough cancer pain as evidenced by significantly increased systemic exposure and reduced times to peak plasma values. FPNS exhibited the most favourable tolerability profile.

Telfer, P. T., C. Lahoz, et al. (2009). "Intranasal diamorphine for acute sickle cell pain." Arch Dis Child.

            The painful crisis is the commonest acute presentation of sickle cell disease (SCD), yet effective pain control in hospital is often delayed, inadequate and dependent on injected opiates. Intranasal diamorphine (IND) has been used in paediatric emergency departments for management of acute pain associated with fractures, but the analgesic effect is short-lived. We evaluated its efficacy and safety when given in combination with intravenous or oral morphine for rapid analgesia for children presenting to our emergency department with painful crisis of SCD. In phase one, nine patients received IND plus intravenous morphine. In phase two, thirteen received IND plus oral morphine. There was a rapid improvement in pain score, the proportions in severe pain at t=0,15,30 and 120 minutes in Phase 1 were 78%, 11%, 0% and 11%; in Phase 2 , 77%, 30%,15% and 0%. There were no serious side effects and questionnaire scores indicated that children found IND effective and acceptable. IND can be recommended for acute control of sickle pain in children presenting to hospital.


Tschirch, F. T., K. Gopfert, et al. (2007). "Low-dose intranasal versus oral midazolam for routine body MRI of claustrophobic patients." Eur Radiol 17(6): 1403-10.

            The purpose of this study was to assess prospectively the potential of low-dose intranasal midazolam compared to oral midazolam in claustrophobic patients undergoing routine body magnetic resonance imaging (MRI). Seventy-two adult claustrophobic patients referred for body MRI were randomly assigned to one of two treatment groups (TG1 and TG2). The 36 patients of TG1 received 7.5 mg midazolam orally 15 min before MRI, whereas the 36 patients of TG2 received one (or, if necessary, two) pumps of a midazolam nasal spray into each nostril immediately prior to MRI (in total, 1 or 2 mg). Patients' tolerance, anxiety and sedation were assessed using a questionnaire and a visual analogue scale immediately before and after MRI. Image quality was evaluated using a five-point-scale. In TG1, 18/36 MRI examinations (50%) had to be cancelled, the reduction of anxiety was insufficient in 12/18 remaining patients (67%). In TG2, 35/36 MRI examinations (97%) were completed successfully, without relevant adverse effects. MRI image quality was rated higher among patients of TG2 compared to TG1 (p<0.001). Low-dose intranasal midazolam is an effective and patient-friendly solution to overcome anxiety in claustrophobic patients in a broad spectrum of body MRI. Its anxiolytic effect is superior to that of the orally administrated form.


Tschirch, F. T., K. Suter, et al. (2008). "Multicenter trial: comparison of two different formulations and application systems of low-dose nasal midazolam for routine magnetic resonance imaging of claustrophobic patients." J Magn Reson Imaging 28(4): 866-72.

            PURPOSE: To prospectively assess and compare two formulations and methods of administration of low-dose nasal midazolam for the treatment of claustrophobic patients undergoing magnetic resonance imaging (MRI) as part of a multicenter Phase III trial. MATERIALS AND METHODS: In all, 108 consecutive adult claustrophobic patients were randomly assigned to one of two treatment groups (multidose group: MDG, unit-dose group: UDG). MDG encompassed 55 patients who received intranasally a 0.5% midazolam formulation into each nostril (total dose, 1.0 mg), whereas the 53 patients in UDG received a 1% midazolam formulation into only one nostril (total dose, 1.0 mg). This initial dose could be repeated once. Patient tolerance and anxiety were assessed using a questionnaire and a visual analog scale immediately before and after MRI. Image quality was evaluated using a five-point scale. RESULTS: In all, 53/55 MR examinations (96%) with MDG and 52/53 (98%) with UDG were completed successfully. The dose of 1 mg had to be repeated significantly less often in UDG compared to MDG (4/53, 8% vs. 13/55, 24%; P = 0.003). The image quality of all MR examinations was rated good to excellent, and slightly better in UDG (P = 0.045). CONCLUSION: Nasally applied low-dose midazolam is a patient-friendly solution to facilitate MRI of claustrophobic patients. The nasal spray of UDG is superior to that of MDG with a necessity of additional dosing.


Watanabe, S., J. Pereira, et al. (2008). "A randomized double-blind crossover comparison of continuous and intermittent subcutaneous administration of opioid for cancer pain." J Palliat Med 11(4): 570-4.

            ABSTRACT Although the preferred route of opioid administration is oral, patients with cancer often require an alternative route. Options include continuous subcutaneous infusion (CSCI) or regularly scheduled intermittent subcutaneous injections (ISCI). CSCI maintains steady drug levels, theoretically avoiding the "bolus effect" of nausea and sedation immediately post-dose, and breakthrough pain prior to the next dose. However, portable infusion pumps can be costly to use. The Edmonton Injector is an inexpensive portable device for ISCI. CSCI and ISCI have not been directly compared. The objective of this trial was to compare CSCI and ISCI of opioid for treatment of cancer pain. Patients were recruited from two tertiary palliative care units. Eligibility criteria included stable cancer pain requiring opioid therapy, need for parenteral route, and normal cognition. Patients were randomly assigned to receive opioid by CSCI by portable pump or ISCI by Edmonton Injector for 48 hours, followed by crossover to the alternative modality for 48 hours. During each phase, placebo was administered by the alternative modality. The study was closed after 12 patients were entered, due to slow accrual. Eleven patients completed the study. There were no differences between CSCI and ISCI in mean visual analogue score (VAS) for pain, nausea or drowsiness; categorical rating score of pain; number of breakthrough opioid doses per day; global rating of treatment effectiveness; or adverse effects. In all cases, patients and investigators expressed no preference for one modality over another. Further research is required to confirm that opioid administration by CSCI and ISCI provide similar analgesic and adverse effects.


Wolfe, Tr, et al. (2006). "Intranasal midazolam therapy for pediatric status epilepticus." Am J Emerg Med 24(3): 343-6.

            Prolonged seizure activity in a child is a frightening experience for families as well as care providers. Because duration of seizure activity impacts morbidity and mortality, effective methods for seizure control should be instituted as soon as possible, preferably at home. Unfortunately, parenteral methods of medication delivery are not available to most caregivers and rectal diazepam, the most commonly used home therapy, is expensive and often ineffective. This brief review article examines recent research suggesting that there is a better way to treat pediatric seizures in situations where no intravenous access is immediately available. Intranasal midazolam, which delivers antiepileptic medication directly to the blood and cerebrospinal fluid via the nasal mucosa, is safe, inexpensive, easy to learn by parents and paramedics, and provides better seizure control than rectal diazepam.


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.


Zeppetella, G. (2000). "Nebulized and intranasal fentanyl in the management of cancer-related breakthrough pain." Palliat Med 14(1): 57-8.


Zeppetella, G. and M. D. Ribeiro (2006). "Opioids for the management of breakthrough (episodic) pain in cancer patients." Cochrane Database Syst Rev(1): CD004311.

            BACKGROUND: Breakthrough pain is a transient increase in pain intensity over background pain. It is a common and distinct component of cancer pain that can have a negative impact for both the patient and carers' quality of life. Breakthrough pain is usually related to background pain and is typically of rapid onset, severe in intensity, and generally self-limiting with an average duration of 30 minutes. At present the current approach to managing breakthrough pain is using supplemental analgesia (also known as rescue medication) at a dose proportional to the total around-the-clock (ATC) opioid dose. OBJECTIVES: This review explores and assesses the evidence for the use of opioids in the management of breakthrough pain in patients with cancer. SEARCH STRATEGY: MEDLINE (1966 to 2005), EMBASE (1980 to 2005), CancerLit (1993 to 2005), CINAHL (1982 to 2005) and Cochrane databases were searched. Handsearching of medical journals and reference from key textbooks was undertaken and drug companies contacted for unpublished data. There was no language restriction. Date of most recent search: January 2005. SELECTION CRITERIA: Randomized controlled trials of opioids used as rescue medication against active or placebo comparator in patients with cancer pain were included. Outcome measures sought were reduction in pain intensity measured by an appropriate scale, adverse effects, attrition, patient satisfaction and quality of life. There were no language restrictions. DATA COLLECTION AND ANALYSIS: Eligible studies were selected and examined independently by the two reviewers. Full text was retrieved if any uncertainty about eligibility remained. Non-English texts were screened. Quality assessment and data extraction were conducted using standardised data forms. Drug and placebo dose, titration, route and formulation were compared and detail of all outcome measures (if available) recorded. MAIN RESULTS: Four studies (393 participants) met the inclusion criteria, all were concerned with the use of oral transmucosal fentanyl citrate (OTFC) in the management of breakthrough pain. Two studies examined the titration of OTFC, one study compared OTFC to normal release morphine and one study compared OTFC to placebo.OTFC was shown to be an effective treatment for breakthrough pain. When compared to placebo and morphine, participants gave lower pain intensity scores and higher pain relief scores for OTFC at all time points. Global assessment scores also favoured OTFC. AUTHORS' CONCLUSIONS: There is evidence that OTFC is an effective treatment in the management of breakthrough pain. The randomised trial literature for the management of breakthrough pain is small and no trials were found for other opioids. Given the importance of this subject, more trials need to be undertaken.