Patient	Medical	Headache	Associated
Identifier	History¹	History²	Symptoms³	Treatment⁴	Results⁵

P#1		Posterior Migraine	Mild Nausea	R 0.75%	Initial pain: 8
			Photophobia	2 Sprays	Pain 10 min post-treatment: 0
					No rebound up to 24 hours
P#2	Head Trauma	Constant		R 0.75%	No Relief⁶
	Resulting From	Headache for circa		2 cc Drops
	Auto Accident	28 years
P#3	Meningitis circa	Monthly Head-		R 0.75%	Transient Improvement⁶
	26 years pre-	aches of circa 3		2 cc Drops
	treatment	day duration
P#4	Post Partum	Migraine		R 0.75%	Initial pain: 9
	Headaches			2 cc Drops	Pain 3 min post-treatment: 0
					No rebound up to 24 hours
P#5		Posterior and	Nausea	R 0.75%	Initial pain: 9
		Lateral Migraine	Photophobia	2 cc Drops	Pain 15 min post-treatment: 0
					No rebound up to 24 hours
P#6	Post Partum	Temporal and		R 0.75%	Initial pain: 8
	Headache	Frontal Headache		Sat'd Cotton	Pain 5 min post-treatment: 0
				Swab	No rebound up to 24 hours
P#7		Temporal and	Visual	R 0.75%	Initial pain: 10
		Frontal Headache	Changes	Sat'd Cotton	Pain 2 min post-treatment: 0
		of 2-3 Day		Swab	No rebound up to 24 hours or up
		Duration			to 48 hours
P#8		Patient's First	Loss of Vision	R 0.75%	Initial pain: 10
		Vascular	Bed-ridden	Sat'd Cotton	Pain 10 min post-treatment: 0
		Headache Episode		Swab	Pain 24 hours post-treatment: 1
		(CT scan ruled out			(this pain was relieved by
		subarachnoid			administering a 325 milligram
		hemorrhage)			Tylenol ™ (McNeil-PPC, Inc.,
					Fort Washington, PA) tablet)
					No rebound up to two weeks
P#9		Migraine		R 0.75%	Initial pain: 8.5
				Sat'd Cotton	Pain 5 min post-treatment: 1
				Swab	No rebound up to 3 days
P#10		Migraine	Nausea	R 0.75%	Initial pain: 9
			Photophobia	Sat'd Cotton	Pain 3 min post-treatment: 0
				Swab	No rebound up to one week
P#11		Occipital	Must lie down	R 0.75%	Initial pain: 9
		Headache few		2 cc Drops	Pain 15 min post-treatment: 5
		times per year			Pain 60 min post-treatment: 0
					No rebound up to one week
P#12		Migraine		L 2.0%	Initial pain: 7
				1 cc Drops	Pain 5 min post-treatment: 2
					Pain 45 min post-treatment: 6^B
P#13	Marfan's	Migraine	Mild Nausea	R 0.75%	Initial pain: 6
	Syndrome			2 Sprays	Pain 30 min post-treatment: 0⁶
					No rebound up to 24 hours
P#14		Migraine	Nausea	R 0.75%	Initial pain: 8
		(Worst during	Photophobia	Sat'd Cotton	Pain 3 min post-treatment: 0
		menses)	Visual changes	Swab	Pain 5 min post-treatment: 2
					Pain 18 hours post-treatment: 8
					(After 18 hrs, treated w/spray)
				Retreated with	Pain following spray: 0⁶
				2 Sprays	No rebound up to 48 hours
P#15	Viral	Sinus Headache	Vertigo	L 2.0%	Initial pain: 6
	Gastrointestinal		developed	1 cc Drops	Pain 15 min post-treatment: 0
	Disturbance		after sneeze		Pain 30 min post-treatment: 6
P#16	Post Partum	Post Dural		L 2.0%	Initial pain: 8
	Headache	Puncture		1 cc Drops	Pain 15 min post-treatment: 4⁶
		Headache
P#17		Migraine	Nausea	R 0.75%	Initial pain: 8
			Photophobia	2 Sprays	Pain 15 min post-treatment: 2
					Pain 20 min post-treatment: 0⁶
					No rebound up to 48 hours
P#18		Migraine	Visual changes	R 0.75%	Initial pain: 9
				Sat'd Cotton	Pain 3 min post-treatment: 0
				Swab
P#19	Lumbar Disc	Migraine		R 0.75%	Initial pain: 9
	Surgery			Sat'd Cotton	Pain 1 min post-treatment: 0
				Swab	No rebound up to 48 hours
P#20	Congenital	Migraine	Nausea	R 0.75%	Initial pain: 8
	Megacolon		Vomiting	Sat'd Cotton	Pain 3 min post-treatment: 0
				Swab	No rebound up to one week
P#21		Migraine	Nausea	R 0.75%	Initial pain: 10
				Sat'd Cotton	Pain 3 min post-treatment: 1
				Swab	Pain 5 min post-treatment: 0
					No rebound up to one week
P#22		Cervical and		R 0.75%	Initial pain: 8
		Occipital		Sat'd Cotton	Pain 10 min post-treatment: 0
		Headache		Swab	No rebound up to 24 hours
P#23	Cervical Spine	Cervical and	Nausea	R 0.75%	Initial pain: 9
	Pain	Occipital		Sat'd Cotton	Pain 5 min post-treatment: 1
		Headache		Swab	No rebound up to 24 hours
P#24		Migraine		R 0.75%	Initial pain: 9
				Sat'd Cotton	Pain 3 min post-treatment: 0
				Swab
P#25		Recurrent Parietal	Nausea	R 0.75%	Initial pain: 10
		and Occipital	Visual changes	Sat'd Cotton	Pain 3 min post-treatment: 0
		Headaches,		Swab	No rebound up to one week
		Bilateral Temporal
		Headaches
P#26		Migraine	Nausea	R 0.75%	Initial pain: 10
			Photophobia	Sat'd Cotton	Pain 5 min post-treatment: 0
				Swab	No rebound up to 24 hours
P#27		Recurrent Frontal,	Nausea	R 0.75%	Initial pain: 10
		Parietal,	Photophobia	Sat'd Cotton	Pain 8 min post-treatment: 0
		Temporal, and		Swab	No rebound up to 48 hours
		Occipital
		Headaches
P#28		Migraine	Nausea	R 0.75%	Initial pain: 9
			Visual changes	Sat'd Cotton	Pain 5 min post-treatment: 0
				Swab	No rebound up to 48 hours
P#29		Migraine	Nausea	R 0.75%	Initial pain: 10
			Photophobia	Sat'd Cotton	Pain 5 min post-treatment: 0
				Swab	No rebound up to 24 hours
P#30	Temporal	Migraine	Nausea	R 0.75%	Initial pain: 9
	Arteritis, Steroid			Sat'd Cotton	Pain 10 min post-treatment: 1
	Use			Swab	No rebound up to 18 hours
P#31		Migraine		R 0.75%	Initial pain: 9
				Sat'd Cotton	Pain 2 min post-treatment: 1
				Swab	No rebound up to 24 hours
P#32	Chemotherapy	Migraine	Nausea	R 0.75%	Initial pain: 10
				Sat'd Cotton	Pain 15 min post-treatment: 0
				Swab
P#33	Hypertension,	Migraine	Nausea,	R 0.75%	Initial pain: 9
	Controlled Diet		Photophobia,	2 Metered	Pain 5 min post-treatment: 5
			Visual changes	Sprays	Pain 30 min post-treatment: 3
					Pain 90 min post-treatment: 0
					(Patient presented one week
					later)
		Migraine		2 Metered	Initial pain: 10
				Sprays	Pain 15 min post-treatment: 5
					Pain 30 min post-treatment: 4
					Pain 90 min post-treatment: 0
					No rebound up to one week
P#34	Major	Migraine	Nausea,	R 0.75%	Initial pain: 7
	Depression,		Photophobia	2 Metered	Pain 20 min post-treatment: 3
	Chronic			Sprays	(Then repeated treatment using
	Hepatitis C				two metered sprays)
				2 Metered	Pain 5 min post-treatment: 0
				Sprays	(Patient presented seven hours
					later)
				2 Metered	Initial pain: 2
				Sprays	Pain 10 min post-treatment: 0
					No rebound up to 24 hours
P#35	Head Trauma	Migraine	Nausea,	R 0.75%	Initial pain: 8
			Visual changes	2 Metered	Pain 30 min post-treatment: 6
				Sprays	Pain 60 min post-treatment: 2
P#36	Complaints of	Migraine	Nausea,	R 0.75%	Initial pain: 9
	“Stuffy Nose”		Photophobia,	2 Metered	Pain 5 min post-treatment: 7
			Visual changes	Sprays	Pain 30 min post-treatment: 5
P#37		Atypical Right	Nausea,	R 0.75%	Initial pain: 7
		Side Headache	Photophobia,	2 Metered	Pain 30 min post-treatment: 3
		Behind Eye	Intense Eye	Sprays	Pain 45 min post-treatment: 0
			Pain &		(Patient presented three days
			Pressure		later)
				2 Metered	Initial pain: 2
				Sprays	Pain 10 min post-treatment: 0
					No rebound up to 48 hours
P#38	Head Trauma	Migraine		R 0.75%	Initial pain: 3
				2 Metered	Pain 30 min post-treatment: 0
				Sprays
P#39		Migraine	Nausea	R 0.75%	Initial pain: 9
				2 Sprays	Pain 2 min post-treatment: 0
					No rebound up to 48 hours
P#40		Migraine	Mild Nausea	R 0.75%	Initial pain: 10
				Sat'd Cotton	Patient exhibited apparent
				Swab	allergic reaction between 5 and
					15 minutes post-treatment
					Pain 20 min post-treatment: 3
					Pain 30 min post-treatment: 5
					Level 5 pain endured 8 hours
P#41	Head Trauma	Recurrent	Nausea,	R 0.75%	Initial pain: 8
		Headaches	Photophobia,	Sat'd Cotton	Pain 20 min post-treatment: 0
			Perceived	Swab	No rebound up to 48 hours
			‘Whistling
			Sounds’
P#42		Migraine	Perceived	R 0.75%	Initial pain: 9
			‘Flashing	Sat'd Cotton	Pain 2 min post-treatment: 0
			Lights’	Swab	No rebound up to one week






# delivery of # millimeters of the indicated solution via the modified nasal drip method described herein; “Sat'd Cotton Swab” refers to delivery of the indicated solution using a standard cotton swab saturated with the indicated solution as described herein; “2 Metered Sprays” refers to delivery of less than about 0.5 milliliter of the indicated solution delivered by a combination of two sprays into each nostril of the patient using a sterile metered-dose spray bottle containing
# the solution.

[0262]

TABLE 2


Demographic and Pretreatment Characteristics of Patients.

Characteristic	Value

Mean Age (Standard Error; Range)	45.1 years (±2.1 years; 22-67)
Gender Male	17 (45.9%)
Female	20 (54.1%)
Duration of Current Headache, hours	23.2 (±4.1)
(Standard Error)
Mean Pain Level on 10-Point Scale	8.64 (±0.223; 8.18-9.09)
(Standard Error; 95% conf. interval)
Patients Experiencing Nausea	23 (62.1%)
Patients Experiencing Photophobia	14 (37.8%)

Thirty-four of the thirty-seven (92%) migraine patients treated with ropivacaine experienced significant (i.e. certainly greater than 50%) reduction of migraine severity. Complete relief followed ropivacaine administration in 72% of the patients. Photophobia, nausea, and pain were simultaneously eliminated in migraine patients who experienced each of these symptoms. Rebound was evident in only two of the responding patients, meaning that the rebound rate was only 5.4%. Adverse effects of ropivacaine administration were minimal: one patient experienced an allergic response to ropivacaine administration, which response consisted of short-lived tachycardia, dizziness, and wheezing, all of which endured for about twenty minutes before subsiding. Even this patient who experienced an allergic response experienced a measurable reduction of migraine pain within twenty-five minutes post-treatment.[0263]

Pain Relief Effected by Cotton-Swab-Application of Ropivacaine[0264]

Among the twenty-four patients to whom ropivacaine was dorsonasally administered using a cotton swab, the mean pain severity rating prior to administration of ropivacaine was 9.06±0.16 points out of a possible 10 points (mean±standard error). The mean post-administration pain severity rating at the time of peak effect was 0.33±0.14 points out of a possible 10 points. Thus, dorsonasal administration of ropivacaine using a cotton swab resulted in a mean peak headache severity rating reduction of 8.73±0.249 points. The mean time that elapsed between the time of treatment and the perception by the patient of the peak effect was 7.41±1.47 minutes. Every patient in this group responded to treatment, 95% of the patients achieving a pain severity rating of zero or one, and 72% of patients achieving a pain severity rating of zero. One patient in this group experienced rebound of headache pain eighteen hours post-treatment. Thus, dorsonasal administration of ropivacaine using a cotton swab causes significant pain reduction in 100% of migraine patients, with rebound occurring in only 4% of patients.[0265]

Pain Relief Effected by Nasal-Drip-Application of Ropivacaine[0266]

Dorsonasal administration of ropivacaine effected by delivery of nasal drops resulted in a mean peak headache severity rating reduction of 9.00 points out of a possible 10 points in the three patients so treated. The mean time that elapsed between the time of treatment and the perception by the patient of the peak effect was 26.00±17.37 minutes. None of the three patients experienced migraine rebound.[0267]

Pain Relief Effected by Nasal-Spray-Application of Ropivacaine[0268]

Dorsonasal administration of ropivacaine effected by delivery using the nasal spray method resulted in a mean peak headache severity rating reduction of 6.22±0.66 points out of a possible 10 points in the ten patients so treated. The mean time that elapsed between the time of treatment and the perception by the patient of the peak effect was 33.9±8.48 minutes. Of the ten migraine patients treated by intranasal spray, all experienced significant reduction in headache pain severity. The majority of these patients experienced complete headache pain relief and did not experience rebound. The remainder experienced a mean headache pain severity rating reduction of 87.5±6.49%. One of the ten patients to whom ropivacaine was administered using a spray bottle experienced a separate episode of migraine one week later.[0269]

Comparison of Administration of Ropivacaine by Cotton Swab, by Nasal Drops, and by Nasal Spray[0270]

The results obtained in patients who were administered ropivacaine by the three methods described herein are summarized in Tables 3 and 4.[0271]

TABLE 3


Effect of the Route of Ropivacaine Administration on Severity of
Migraine Pain. Pain Ratings and Pain Relief are measured using a
10-point pain scale, as described herein.

Method of	Pain Rating Prior	Pain Rating After
Delivery	to Administration	Administration	Pain Relief

Cotton Swab	9.06	0.33	8.73
Nasal Drops	9.00	0.00	9.00
Nasal Spray	7.22	1.00	6.22

[0272]

TABLE 4


Effect of the Route of Ropivacaine Administration of Severity of
Migraine Pain.

		Mean	Mean Time	Rate of Pain
	Number	Reduction in	Until	Relief (HIS
	of	Pain Rating	Maximal	points per
Method of Delivery	Patients	(IHS points)	Effect	minute)

Cotton Swab	24	8.64	7.41	2.32
(Standard Error)		(±0.25)	(±1.46)
95% confid. interval		8.12-9.16	4.37-10.4
Nasal Drops	3	9.00	26.0	1.25
(Standard Error)		(0)	(±12.3)
95% confid. interval		5.89-10.6	0-100
Nasal Spray	10	6.22	33.9	0.287
(Standard Error)		(±0.66)	(±8.48)
95% confid. interval		4.69-7.75	14.31-53.46

Comparison of the Therapeutic Effect of Dorsonasally-Administered Ropivacaine and the Therapeutic Effect of Intranasally-Administered Lidocaine[0273]

The anesthetic effect of 0.75% (w/v) ropivacaine-HCl is approximately equivalent to that of 3% (w/v) lidocaine. Intranasal spray administration of 1-2 milliliters of a 4% (w/v) lidocaine solution was 55% effective to reduce pain associated with migraine (Maizels et al., 1996, J. Amer. Med. Assoc. 276:319-321). By comparison, as described herein, dorsonasal spray administration of a 0.75% (w/v) ropivacaine solution was 100% effective to reduce pain associated with migraine. Furthermore, when dorsonasal administration of the ropivacaine solution was effected by topical application using a cotton swab saturated with the solution, reduction of migraine pain was achieved in 100% of patients. Preliminary data indicate that bupivacaine exhibits efficacy similar to that of ropivacaine for the relief of headache pain associated with migraine.[0274]

A comparison of ropivacaine and lidocaine on the basis of migraine pain relief per unit weight is provided in Table 5. This comparison indicates that dorsonasally spray-administered ropivacaine is 2.4 times as potent as intranasally spray-administered lidocaine, and that dorsonasally swab-administered ropivacaine is more than 15 times as potent as intranasally spray-administered lidocaine. Furthermore, as indicated in Table 5, the rate of migraine rebound is much lower following dorsonasal administration of ropivacaine, whether administered by nasal spray or by cotton swab, than it is following intranasal administration of lidocaine. Thus, the data presented herein indicate that ropivacaine is a much more efficacious agent for migraine pain relief than is lidocaine and that treatment of migraine by dorsonasal ropivacaine administration has a significantly lower rebound rate than treatment by intranasal administration of lidocaine.[0275]

Table 5. Comparison of the efficacy of migraine treatment by dorsonasal ropivacaine administration and the efficacy by intranasal lidocaine administration. “Rate” indicates the rate of migraine pain reduction per minute per gram of drug administered to the patient. Pain was rated using a 10-point pain scale, as described herein.[0276]



	Route of	Rate of	Relative	Rebound
Drug	Administration	Pain Relief	Efficacy¹	Rate

Lidocaine	Intranasal Spray	10.0	1.00	42%
Ropivacaine	Dorsonasal Spray	24.5	2.45	10%
Ropivacaine	Dorsonasal Swab	155	`15.5	4%

Comparison of the Therapeutic Effect of Ropivacaine and the Therapeutic Effects of Other Anti-Migraine Pharmaceutically Active Agents[0277]

In FIG. 3, the data obtained from the procedures performed in this Example are presented and compared with recently reported data obtained for administration of lidocaine to migraine patients (Maizels et al., 1996, J. Amer. Med. Assoc. 276:319-321) or administration of sumatriptan to migraine patients (The Subcutaneous Sumatriptan International Study Group, 1991, New Eng. J. Med. 325:316-321). Administration of ropivacaine resulted in an earlier onset of relief and a higher response rate than did administration of sumatriptan. Although the time of onset of relief using ropivacaine was roughly equal to the time of onset of relief using lidocaine, administration of ropivacaine treatment resulted in a nearly two-fold greater response rate than did administration of lidocaine. The response rate obtained by administration of ropivacaine to migraine patients was greater than the response rate obtained by administration of rizatriptan to such patients. In addition, the rebound rate following ropivacaine administration was lower than the rebound rate following rizatriptan administration (Kramer et al., 1997, Headache 36:268-269). The rapid and non-relapsing effects attributable to dorsonasal administration of ropivacaine are not observed following administration of lidocaine or a serotonin receptor agonist administered by the same route (Mills et al., 1997, Ann. Pharmacother. 31:914-915; Moore et al., 1997, Cephalalgia 17:541-550; Kramer et al., 1997, Headache 36:268-269).[0278]

While not wishing to be bound by any particular theory of operation, it is believed that dorsonasally administered ropivacaine inhibited migraine by anesthetizing a DnNS such as the SPG. Ropivacaine is ideally suited for anesthesia of a DnNS in general, and for migraine relief in particular. Ropivacaine exhibits intermediate lipid solubility and an intermediate half life in vivo, properties that limit possible toxicity. Direct application of ropivacaine to the region of the nasal epithelium overlying the SPG reduces the likelihood of systemic distribution of the compound, thereby limiting the likelihood of numerous side effects. Furthermore, direct application of ropivacaine to the region of the nasal epithelium overlying the SPG reduces the amount of ropivacaine which must be administered in order to provide an effective concentration at the SPG for relief of an acute migraine episode. Ropivacaine and other local anesthetics related to aminoacyl local anesthetics are known to selectively affect sensory neurons, relative to motor neurons, representing another advantage of using ropivacaine in the method of the invention. It is believed that direct administration of ropivacaine to the region of the nasal epithelium overlying the SPG, or to the region of the nasal epithelium near that region, arrests the cascade of neurotransmitter and neuropeptide release and stimulation that lead to neurogenic inflammation observed in the course of an acute migraine episode.[0279]

The ropivacaine molecule has the following structure (III), wherein the carbon atom indicated by the asterisk is a chiral center:[0280]
Cardiotoxicity is a side effect of administration of the R(dextro) enantiomer of ropivacaine, but this side effect is not exhibited by the S(levo) enantiomer (dejong, 1995, Reg. Anesth. 20:474-481). For this reason, ropivacaine is prepared as a sterile solution containing only the S(levo) enantiomer. The bupivacaine molecule also comprises a chiral center, but currently commercially available bupivacaine preparations include both the S and the R enantiomers.[0281]
Many of the patients described in this Example were observed for up to seven days, and 95% of those patients experienced no rebound during this period. This result contrasts with the results obtained following intranasal lidocaine administration. Of the 55% of patients who exhibited relief following intranasal lidocaine administration, at least 42% experienced rebound, usually within one hour post-treatment (Maizels et al., 1996, J. Amer. Med. Assoc. 276:319-321). Similarly, administration of either sumatriptan or rizatriptan resulted in inhibition of pain in 40-50% of patients within two hours post treatment, and patients who were administered either of these compounds frequently experienced rebound (The Subcutaneous Sumatriptan International Study Group, 1991, New Eng. J. Med. 325:316-321; Kramer et al., 1997, Headache 36:268-269).[0282]

EXAMPLE 2

Dorsonasal Administration of Bupivacaine for Inhibition of Acute Migraine Episodes[0283]

The purpose of the experiments described in this Example was to determine the efficacy of dorsonasal administration of bupivacaine for inhibition of acute migraine episodes. Bupivacaine was dorsonasally administered to individual patients experiencing head pain, other symptoms, or both, believed to be associated with an acute migraine episode. Patients assessed head pain prior to and after bupivacaine administration.[0284]

Dorsonasally administered bupivacaine provided rapid arrest of migraine in all seven patients to whom it was administered within 10 minutes or less. Symptoms such as nausea, visual changes, and photophobia associated with acute migraine episodes in the patients were similarly reduced. Six of the seven patients treated using bupivacaine experienced no rebound of their migraine within twenty-four hours of treatment. The other patient experienced a recurrence of head pain four hours following a first administration of bupivacaine and another episode of head pain eight hours following a second administration of bupivacaine. These results demonstrate that dorsonasal administration of bupivacaine is an efficacious method of inhibiting an acute migraine episode.[0285]

The materials and methods used in the procedures performed in this Example were substantially the same as the materials and methods described in Example 1, with the exception that the composition which was administered to the patients described in this example comprised a 0.75% (w/v) solution of bupivacaine.[0286]

The results of treatment of each of the seven patients described in this Example with bupivacaine are presented in Table 6. The organization of and the abbreviations used in Table 6 are analogous to those used in Table 1, with the exception that “B” in the treatment column refers to bupivacaine. These results indicate that dorsonasal administration of bupivacaine is effective to inhibit acute migraine episodes.[0287]

TABLE 6


Summary of Patient Data.

Patient	Medical	Headache	Associated
Identifier	History	History	Symptoms	Treatment	Results

P2#1		Migraine	Nausea	B 0.75%	Initial pain: 5
				2Sprays	Pain	10 min post-treatment: 0
					No rebound up to 24 hours
P2#2		Migraine	Nausea	B 0.75%	Initial pain: 7
			Photophobia	Sat'd Cotton	Pain	5 min post-treatment: 0
				Swab	No rebound up to 24hours
P2#
3		Migraine	Visual Changes and nausea as	B 0.75%	Initial pain: 10
			aura. Followed by head pressure	2 cc Drops	Pain 5 min post-treatment: 1-
					2
			and severe head pain at right		Head pressure persisted
			occipital to front areas		No rebound up to 24 hours
P2#4	Sinus	Migraine		B 0.75%	Initial pain: 8
	Surgery	Triggered		2Sprays	Pain	5 min post-treatment: 0
		by			Recurrence 4 hours post-
					treatmt.
		Chocolate			Pain	5 min post-2nd-treat-
					ment: 0
		Ingestion			Recurrence 8 hours post-
					treatmt.
P2#5		Mixed	Nausea	B 0.75%	Initial pain: 8
		Headache	Photophobia	2Sprays	Pain	10 min post-treatment: 0
					No rebound up to 24 hours
P2#6		Migraine		B 0.75%	Initial pain: 8
				2Sprays	Pain	3 min post-treatment: 0
					No rebound up to 24 hours
P2#7		Migraine	Visual Changes	B 0.75%	Initial pain: 10
				2 cc Drops	Pain 10 min post-treatment: 0
					No rebound up to 24 hours

EXAMPLE 3

Inhibiting a Recurring Cerebral Neurovascular Disorder by Dorsonasally Administering a Long-acting Local Anesthetic Decreases the Frequency and Severity of Subsequent Episodes[0288]

The following studies relate to the methods of decreasing the frequency and severity of CNvD episodes described herein, and involved three patients.[0289]

A 25-year-old female patient, herein designated “patient 3-1” was afflicted with recurring severe migraine, wherein acute migraine episodes were associated with nausea and visual changes. Patient 3-1 generally rated the severity of head pain associated with acute migraine episodes in the range from five to eight using the pain scale described herein. Patient 3-1 experienced, on average, about one acute migraine episode per week prior to beginning dorsonasal ropivacaine therapy. In addition, patient 3-1 also usually experienced about one severe acute migraine episode per month, associated with menses, wherein the severity of head pain was from eight to ten using the pain scale described herein. Patient 3-1 did not respond satisfactorily to administration of beta blockers and sumatriptan.[0290]

Ropivacaine was dorsonasally administered to patient 3-1 using the cotton swab technique described herein. The patient has consistently experienced relief from all of the symptoms of her CNvD episodes within 3 to 5 minutes following administration of ropivacaine, regardless of whether the episodes are associated with menses.[0291]

Patient 3-1 has continued treatment according to this method for about six months. After beginning the ropivacaine treatment, the patient discontinued use of sumatriptan and propanolol. Discontinuing these medications did not result in a loss of efficacy attributable to ropivacaine administration. Starting about three or four months following initiation of ropivacaine administration, the patient noticed a decrease in the initial severity of acute migraine episodes not associated with menses. At about the same time, the patient further noticed a decrease in the frequency with which acute migraine episodes not associated with menses occurred. No decrease in either the initial severity or the frequency of acute migraine episodes associated with menses has been reported by the patient. Patient 3-1 continues to experience relief from the head pain and other symptoms of acute migraine episodes, including those associated with menses, upon administration of ropivacaine.[0292]

A 45-year-old male, herein designated, “patient 3-2,” was afflicted with recurring migraines. The acute migraine episodes began when he was a teenager, and have significantly worsened over the past 15 years. Head pain associated with the patient's acute migraine episodes is typically preceded by visual changes which he describes as a curtain-like wave of scotomata moving from left to right until he is unable to see. The patient then becomes disoriented with respect to time and place and must sit or lay down. Following these prodromal symptoms, a severe headache, rated 10 on the pain scale described herein, begins and typically endures for 45 to 60 minutes. The patient remains completely debilitated for the duration of the headache, unable to move about or walk. As the headache subsides, the patient's vision returns, and the patient is left feeling exhausted, as if he had not slept the night before.[0293]

Following dorsonasal administration of ropivacaine, delivered by the nasal spray method described herein, patient 3-2 noticed an abrupt halt to the progression of visual changes and steady resolution of his visual deficit. The headache rapidly decreased in intensity, decreasing from a pain intensity of 10, using the pain scale described herein, to an intensity of 2-3 within one to two minutes. The headache was completely resolved by fifteen minutes following ropivacaine administration. This patient also noted that he did not feel exhausted following the treated acute migraine episode. After four to six months of dorsonasal ropivacaine therapy, the patient noted that his headaches occurred less frequently, at a rate of approximately one headache every two months or longer. Furthermore, the severity of the headaches that patient 3-2 experienced was significantly reduced following this course of therapy. Prior to the course of dorsonasal ropivacaine therapy, the patient's headaches ordinarily had a pain intensity of about 10; after four to six months of this therapy, the initial headache pain (i.e. even prior to ropivacaine administration) was not greater than about 2. The patient reports significant lifestyle improvement, and is not aware of any other changes, for example changes in diet, sleep, exercise, environment, or medication, that could account for this improvement.[0294]

A 40-year-old female, herein designated, “patient 3-3,” experienced about 3 to 5 recurring migraine episodes per week prior to beginning dorsonasal ropivacaine therapy. The initial severity of these headaches was reported to be 10, using the pain scale described herein. When ropivacaine was administered, using the saturated swab method described herein, to patient 3-3 during a headache episode, the patient reported a decrease in head pain from a rating of 10 to a rating of 0 or 1 within 10 minutes following ropivacaine administration. Furthermore, after three months of dorsonasal ropivacaine treatment, patient 3-3 reported that the frequency of her headache episodes had decreased to about 1 to 2 times weekly and that the initial severity of her headaches was in the range from about 7 to about 8, rather than 10.[0295]

The data described in this Example indicate that dorsonasal administration of ropivacaine to a patient afflicted with a recurring CNvD both inhibits a single episode of the CNvD and decreases the frequency and initial severity of the episodes associated with the recurring CNvD. Thus, the compositions, kits, and methods of the invention are useful for decreasing the frequency with which a patient afflicted with a recurring CNvD experiences a CNvD episode and for otherwise inhibiting the CNvD.[0296]

EXAMPLE 4

Inhibition of Tinnitus by Dorsonasal Administration of Ropivacaine[0297]

The data presented in this example demonstrate that symptoms of tinnitus may be inhibited by dorsonasal administration of a local anesthetic. Ropivacaine was dorsonasally administered to each of three patients using the nasal spray method or the nasal drops method described herein. All three patients experienced inhibition of tinnitus.[0298]

The first patient, herein designated, “patient 4-1,” was a healthy male patient in his thirties who was afflicted with occasional migraines complicated by bilateral tinnitus about once every two to three months. Dorsonasal spray administration of ropivacaine to patient 4-1 relieved the head pain and tinnitus symptoms experienced by this patient within about five minutes following administration.[0299]

The second patient, herein designated, “patient 4-2,” was a male in his forties who was afflicted with chronic head, neck, back, and shoulder pain resulting from trauma sustained during multiple motor vehicle accidents. Patient 4-2 was afflicted with constant head pain for which he used large quantities of intranasally-administered butorphanol. It was believed that the patient's headaches did not have a neurovascular etiology. Patient 4-2 is also afflicted with continuous bilateral tinnitus. Following dorsonasal spray administration of ropivacaine to patient 4-2, the patient reported a decrease in head pain of about 2 points, using the pain scale described herein, and furthermore experienced complete relief from symptoms of tinnitus for a period of 30 to 45 minutes. Interestingly, this patient noted a faster onset and a far more powerful effect on his chronic non-headache pain of intranasally administered butorphanol following intranasal administration of ropivacaine.[0300]

The third patient, herein designated, “patient 4-3,” was a healthy male in his sixties who was afflicted with bilateral tinnitus for over 30 years. Following dorsonasal administration of 1 milliliter of 0.75% (w/v) ropivacaine into each nostril by the nasal drop method described herein, patient 4-3 experienced complete relief from tinnitus symptoms in his left ear and a 50-75% reduction in tinnitus symptoms in his right ear. This patient's relief from and reduction of symptoms persisted for about 30 to 45 minutes, after which period the tinnitus symptoms returned.[0301]

The results of the experiments described in this Example indicate that dorsonasal administration of a local anesthetic inhibits tinnitus. Even though the relief of tinnitus in these three patients was relatively short-lived (relative to migraine relief, as described herein), it must be borne in mind that no effective treatment exists for tinnitus. Thus, the treatment method described herein for tinnitus can be used to provide at least temporary relief to patients who have no effective long-term treatment options. Furthermore, the results presented in this Example suggest that a sustained release preparation of a local anesthetic or a local anesthetic causing a longer duration of anesthesia than ropivacaine may provide a longer period of inhibition of tinnitus than the ropivacaine preparation used in this method.[0302]

EXAMPLE 5

Dorsonasal Administration of Bupivacaine for Treatment of Muscular Headache Episodes[0303]

The purpose of the experiments described in this Example was to determine the efficacy of dorsonasal administration of bupivacaine for inhibition of muscular headaches. Bupivacaine was dorsonasally administered to four individual patients experiencing head pain and other symptoms associated with a severe muscular headache episode. All of the patients had areas of sustained craniocervical muscle contraction and tenderness which was absent in all patients following headache resolution. Patients assessed head pain prior to and after bupivacaine administration. The four patients and their responses were as follows.[0304]

Patient 1[0305]

This patient was a 68-year-old female who experienced classic tension headache symptoms under stress. The patient normally experienced relief of tension headache symptoms following administration of ibuprofen. The patient was administered 0.75% bupivacaine during a tension headache episode, and thereafter experienced relief of her headache symptoms. The patient's pain intensity, as assessed using the pain scale described herein, decreased from about 8 to 0 within about 15 minutes after bupivacaine administration.[0306]

Patient 2[0307]

This patient was a 38-year-old male who experienced typical muscle contraction headache symptoms. The patient normally experienced relief of headache symptoms following administration of acetaminophen. The patient was administered 0.75% bupivacaine during a muscle contraction headache episode, and thereafter experienced relief of his headache symptoms within seven minutes following bupivacaine administration. The patient's pain intensity, as assessed using the pain scale described herein, decreased from about 7 to 0 within about 7 minutes after bupivacaine administration.[0308]

[0309]Patient 3

This patient was a 25-year-old male who experienced cervical neck pain symptoms associated with tension headache. The patient experienced moderate relief of headache symptoms following administration of non-steroidal anti-inflammatory drugs, including ibuprofen. The patient was administered 0.75% bupivacaine during a tension headache episode, and thereafter experienced relief of his headache symptoms. The patient's pain intensity, as assessed using the pain scale described herein, decreased from about 5 to about 1 within about 5 minutes after bupivacaine administration.[0310]

Patient 4[0311]

This patient was a 44-year-old female who experienced tension headaches. The patient was administered 0.75% bupivacaine during a tension headache episode, and thereafter experienced relief of neck pain and bi-temporal tension headache pain symptoms. The patient's pain intensity, as assessed using the pain scale described herein, decreased from about 7 to about 1 within about 5 minutes after bupivacaine administration. Prior to bupivacaine administration, the patient experienced mild residual pain in response to deep palpation of affected neck and temple muscles. This pain was perceived to be markedly decreased following treatment, and muscle knots were no longer perceived 5 minutes after treatment.[0312]

It is recognized that the muscular headache inhibition described in this Example may have been secondary to neurovascular effects of a dorsonasally administered local anesthetic or to effects on one or both of intracranial or extracranial neural or vascular structures, as described herein.[0313]

EXAMPLE 6

Dorsonasal Administration of a Eutectic Mixture of Local Anesthetics[0314]

An amount (0.5-1.0 milliliters) of a commercially available eutectic mixture of local anesthetics (prilocaine/lidocaine, 2.5% (w/v) each; Emla™, Astra USA, Westborough, Mass.) was dorsonasally administered to each of six healthy adults using a syringe having a flexible applicator attached thereto. None of the six adults noted oropharyngeal numbness, unpleasant taste, or any other side effect normally associated with administration of a local anesthetic following intranasal administration.[0315]

The same amount of the mixture was dorsonasally administered to five patients afflicted with headaches. Each of these five patients experienced complete or nearly complete inhibition of head pain and other symptoms of their headaches within ten minutes following administration.[0316]

The disclosures of each and every patent, patent application, and publication cited herein are hereby incorporated herein by reference in their entirety.[0317]

While this invention has been disclosed with reference to specific embodiments, it is apparent that other embodiments and variations of this invention may be devised by others skilled in the art without departing from the true spirit and scope of the invention. The appended claims are intended to be construed to include all such embodiments and equivalent variations.[0318]