WO2019079327A1 - Combination therapies and opioid addiction treatment by administering brivaracetam or levetiracetam and an opioid - Google Patents

Abstract

Disclosed herein are methods of methods of treating pain in a subject, reducing opioid dose without increasing pain to a subject, and decreasing pain in a subject without decreasing an opioid dose.

Description

COMBINATION THERAPIES AND OPIOID ADDICTION TREATMENT BY

ADMINISTERING BRIVARACETAM OR LEVETIRACETAM AND AN OPIOID FIELD

[0001 ] This patent application claims the benefit under 35 U.S.C. §119(e) of U.S. Patent Application Serial No. 62/572,833 entitled "Combination Therapies and Opioid Addiction Treatment by Administering Brivaracetam or Levetiracetam and an Opioid," filed on October 16, 2017, which is incorporated herein by reference in its entirety.

[0002] The disclosure relates to treating pain using a combination of either brivaracetam or levetiracetam, and an opioid. The disclosure is further directed to treating opioid addiction by combination therapy.

BACKGROUND

[0003] Spinal cord injury (SCI) frequently results in severe or disabling pain. Individuals with a SCI suffer anywhere from between 20 and 77% incidence of some level of severe or disabling chronic pain. Davis et al., Clin Orthop 112:76-80 (1975); Richards et al., Pain 8:355-366 (1980); Siddall et al., Spinal Cord 39:63-73 (2001 ); Stormer et al., Spinal Cord 446-455 (1997); Woolsey, J Am Paraplegia 9:39-41 (1986). Subjects suffering from at least some level of severe or disabling chronic pain show reduced rehabilitation potential and tend to have a significant overall reduction in quality of life.

[0004] Neuropathic pain in the CNS (central pain) has proven notoriously difficult to treat, often proving recalcitrant to modern medical and surgical pain treatment procedures. Surgical treatment of specific dorsal root entry zone(s) (DREZ(s)) of the spinal cord are of particular interest. Surgical treatment of a central pain generating DREZ at the level of an injury is believed to disrupt the neural, i.e., electrical, communication and/or generation of aberrant pain signals that result from the injury. Initially, empirical techniques have been used to target DREZ sites for surgical treatment, resulting in modest outcomes for the subject, i.e., DREZ sites at the site of injury targeted for treatment. (Friedman et al., J Neurosurg 65:465-469 (1986); Ishijima et al., Appl Neurophysiol 51 :2-5, 175-187 (1988); Rath et al., Acta Neurochir 138:4, 364-369 (1996); Rath et al., Sterotact Funct Neurosurg 68:1 -4, Pt 1 , 161 -167 (1997)).

[0005] One of the more relevant subject studies using this empirical technique suggests that approximately 50% of subjects so treated achieve good relief from SCI associated pain. (Friedman et al., J Neurosurg. 65:465-469 (1986)). In that series, at-level pain, i.e., pain at the immediate vicinity of the injury, responded best (74% "good results") and below-level pain, i.e., pain below the level of injury, responded poorly (20% "good results").

[0006] Anti-epileptic drugs are often suggested for treating neuropathic pain. Two of these commercially approved compounds, levetiracetam and brivaracetam, are 2-oxo-pyrrolidin-1 -yl bytanamide derivatives that act by binding to synaptic vesicle glycoprotein 2A (SV2A).

However, this class of compounds has been disparaged as a method of treating pain in SCI individuals. Finnerup et al., Scandinavian J. Pain 1 , (2009) S3-S1 1 , described levetiracetam as ineffective in treating pain resulting from spinal cord injury. According to Finnerup et al., "levetiracetam does not relieve neuropathic pain or spasm severity following spinal cord injury." Finnerup et al. further pointed out that the lack of efficacy on the postmastectomy syndrome suggests a lack of interference with mechanisms underlying peripheral postsurgical neuropathic pain as well. Finnerup et al. suggested that it is possible that the pharmacological action of levetiracetam is not involved in neuropathic pain mechanisms and that interference with the SV2A in levetiracetam doses used in humans will have no impact on neuropathic pain.

[0007] Levetiracetam has been shown to have no analgesic or other benefit in subjects with neuropathic pain following SCI. (Finnerup et al.). This suggests that the same would be true for any SV2A-affecting compound, including brivaracetam.

SUMMARY

[0008] In one aspect, the disclosure is directed to a method of reducing opioid dose without increasing pain to a subject in need thereof. The method comprises to the subject a combination therapy comprising brivaracetam or levetiracetam, and an opioid at a dose at least 10% lower than the baseline dose in the absence of brivaracetam or levetiracetam. The subject has no increase in pain on a 0-10 pain scale as compared to administration of the opioid alone at the baseline dose.

[0009] In another aspect, the disclosure is directed to a method of treating pain in a subject. The method comprises administering to the subject a combination therapy comprising both brivaracetam or levetiracetam and an opioid at a dose at least 10% lower than the initial dose in the absence of brivaracetam or levetiracetam. Subsequently, a combination therapy comprising brivaracetam or levetiracetam and the opioid at a maintenance dose at least 10% lower than the baseline maintenance dose in the absence of brivaracetam or levetiracetam is administered. The subject has no increase in pain on a 0-10 pain scale as compared to administration of the opioid alone at the baseline dose.

[0010] In some variations, the opioid can be administered at a dose at least 20% or 30% lower than the baseline does in the absence of brivaracetam or levetiracetam. Further, in some variations, the subject has a decrease in pain of at least 1 , 2, or 3 on a 0-10 pain scale.

[0011] In some variations, is brivaracetam is administered. In other variations, levetiracetam is administered.

[0012] The opioid can be any opioid known in the art. In various aspects, the opioid can be selected from Codeine, Fentanyl, Hydrocodone, Hydromorphone, Methadone, Oxycodone, Oxymorphone, Buprenorphine, Methadone, Morphine, Naltrexone, Nalbuphine, Tapentadol, and Tramadol.

[0013] In some variations, the subject can have a central nervous system injury.

[0014] In some variations, the pain is neuropathic pain.

[0015] These and other variations are further described in the disclosure.

DETAILED DESCRIPTION

[0016] In one aspect, the disclosure is directed to treating central neuropathic pain by administering to a subject in need thereof a combination therapy of an opioid and

brivaracetam or levetiracetam. In some instances, brivaracetam or levetiracetam is administered at a lower daily dosage, reduced dosage schedule, and/or lower reduced dosage over a time course. The opioid can be any opioid known in the art. In particular, the opioid can be used to treat acute pain or chronic pain, and more specifically neuropathic pain. In some variations, the opioid is administered at a lower daily dosage, reduced dosage schedule, and/or lower reduced dosage over a time course. The combination therapy surprisingly results in a reduced drug load to the subject.

[0017] In a second aspect, the disclosure is directed to reducing opioid addiction by administering to a subject in need thereof brivaracetam or levetiracetam in combination with the opioid. The opioid can be administered at a lower dose than when administered alone. Alternatively, the dose of the opioid can be reduced over a period of time until a lower dosage plateau is reached.

[0018] In a third aspect, the disclosure is directed to reducing pain in a subject on an opioid therapeutic regimen. For example, the subject can be on a regimen adapted to treat chronic pain. Due to the chronic nature of pain treatment, the amount of opioid administered to such subjects can in some cases be substantially greater than the amounts approved for administration on various product labels. Brivaracetam or levetiracetam is administered, and an opioid is also administered. In such instances, the subject has a decrease in pain of at least 1 on a 0-10 pain scale as compared to administration of the opioid in the absence of brivaracetam or levetiracetam. In various aspects, the opioid dose is maintained. The pain scale is generally known in the art, for example as described by Farrar et al., Clinical importance of changes in chronic pain intensity measured on an 11 -point numerical pain rating scale, Pain 94 (2001 ) 149 - 158, and Hawker et al., Measures of Adult Pain, Arthritis Care & Research Vol.63 No. S1 1 , November 201 1 (S240 - S252).

[0019] The term "subject" as used herein, refers to an animal, alternatively a mammal, alternatively a human adult, child or infant, who has been the object of treatment, observation or experiment. In one embodiment, the subject to be treated is a human. [0020] It will be appreciated that references herein to "treatment" extend to prophylaxis, prevention of recurrence and suppression or amelioration of symptoms (whether mild, moderate or severe) as well as the treatment of established conditions.

[0021] The term "therapeutically effective amount" as used herein, means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of one or more of the symptoms of the disease or disorder being treated; and/or reduction of the severity of one or more of the symptoms of the disease or disorder being treated.

[0022] Without wishing to be limited to a particular mechanism or mode of action, brivaracetam and levetiracetam may potentiate the effect of narcotics, allowing a substantial reduction in opioid dose and a substantial decrease in neuronal excitability. SV2A may be the cause of the hyperactive pain neurons by acting negatively on opioid receptor binding of opioid ligand, thereby causing the body's reflex response to release more SML4 to bond on the opioid receptors.

[0023] Further, and again without wishing to be limited to a particular mechanism or mode of action, brivaracetam and levetiracetam may potentiate the effect of narcotics, resulting in a decrease in required narcotic dose. This can be true for any kind of pain, including acute pain, chronic pain, neuropathic pain, pain resulting from SCI, and post-surgical pain.

[0024] Central pain can result from spontaneous neuronal hyperexcitability in Rexed Layers 1 -3 of the spinal cord. In normal pain states, opioids can act on the opioid receptors of hyperexcitable neurons in these same Rexed Layers to relieve pain (e.g. post-surgical pain, broken leg, etc.) by decreasing neuronal hyperexcitability. Hyperexcitable neurons in these Rexed Layers are caused by the firing of injured peripheral neurons (e.g, from a broken leg) in these normal pain states.

[0025] However, it is well known that opioids are relatively ineffective at relieving neuropathic pain. These same opioid receptors, which normally decrease the hyperexcitability of the pain producing neurons in Rexed Layers 1 -3 in normal pain states, fail to do so in neuropathic pain states. This effect is observed in both clinical data and the ineffectiveness of opioids in having an effect on hyperactive DREZ recordings in subjects taking high doses of narcotics.

[0026] The combination therapy of brivaracetam and levetiracetam and opioid results in reduced dose requirements for the opioid. As described in Example 1 , the combination therapy of brivaracetam resulted in a decrease the daily narcotic load by 40% and with an improvement of pain efficacy from 9-10 to a 6 on a pain scale of 0-10. Without wishing to be held to a particular mechanism or mode of action, this unexpected and profound synergistic effect may have allowed the opioid to act more effectively with the opioid receptor, significantly decreasing pain as well as the dose of opioid administered. [0027] In some particular embodiments, the compound is

(2S)-2-[(4R)-2-oxo-4-propylpyrrolidinyl]butanamide (brivaracetam).

[0028] In some particular embodiments, the compound is (S)

-alpha-ethyl-2-oxo-1 -pyrrolidineacetamide (levetiracetam).

[0029] As used herein, the terms "combination therapy", "co-therapy", and "adjunctive therapy" refers to treatment of a subject in need thereof by administering brivaracetam or levetiracetam and an opioid by any suitable means, simultaneously, sequentially, separately or in a single pharmaceutical formulation. Thus, according to a further aspect of the disclosure there is provided brivaracetam or levetiracetam and an opioid for use in co-therapy, adjunctive therapy or combination therapy wherein brivaracetam or levetiracetam and opioid are administered simultaneously, sequentially, separately or in a single pharmaceutical formulation.

[0030] When administration is sequential, either compound may be administered first. When administration is simultaneous, the combination may be administered either in the same or different pharmaceutical composition.

[0031] When combined in the same formulation it will be appreciated that the two compounds (i.e., brivaracetam or levetiracetam, and the opioid) are stable and compatible with each other and the other components of the formulation. When formulated separately the two compounds may be provided in any convenient formulation, conveniently in such manner as are known for such compounds in the art.

[0032] Examples of pain include chronic inflammatory pain (e.g. pain associated with rheumatoid arthritis, osteoarthritis, rheumatoid spondylitis, gouty arthritis and juvenile arthritis); musculoskeletal pain; lower back and neck pain; sprains and strains; neuropathic pain; sympathetically maintained pain; myositis; pain associated with cancer and fibromyalgia; pain associated with migraine; pain associated with influenza or other viral infections, such as the common cold; rheumatic fever; pain associated with functional bowel disorders such as non-ulcer dyspepsia, non-cardiac chest pain and irritable bowel syndrome; pain associated with myocardial ischemia; post-operative pain; headache; toothache; and dysmenorrhea.

[0033] In one variation, the composition of the disclosure is used in the treatment of neuropathic pain. Neuropathic pain syndromes can develop following neuronal injury and the resulting pain may persist for months or years, even after the original injury has healed. Neuronal injury may occur in the peripheral nerves, dorsal roots, spinal cord or certain regions in the brain. Neuropathic pain syndromes are traditionally classified according to the disease or event that precipitated them. Neuropathic pain syndromes include: diabetic neuropathy; sciatica; non-specific lower back pain; multiple sclerosis pain; fibromyalgia; HIV-related neuropathy; post-herpetic neuralgia; trigeminal neuralgia; and pain resulting from physical trauma, amputation, cancer, toxins or chronic inflammatory conditions. The symptoms of neuropathic pain are incredibly heterogeneous and are often described as spontaneous shooting and lancinating pain, or ongoing, burning pain. In addition, there is pain associated with normally non-painful sensations such as "pins and needles" (paraesthesias and dysesthesias), increased sensitivity to touch (hyperesthesia), painful sensation following innocuous stimulation (dynamic, static or thermal allodynia), increased sensitivity to noxious stimuli (thermal, cold, mechanical hyperalgesia), continuing pain sensation after removal of the stimulation (hyperpathia) or an absence of or deficit in selective sensory pathways (hypoalgesia).

[0034] According to a further aspect of the disclosure, there is provided brivaracetam or levetiracetam and an opioid for use in the treatment of pain, such as neuropathic pain, wherein brivaracetam or levetiracetam and opioid are administered simultaneously, sequentially, separately or in a single pharmaceutical formulation. In one embodiment of this aspect of the disclosure, brivaracetam or levetiracetam and opioid are as defined hereinbefore for other aspects of the disclosure.

[0035] According to a further aspect of the disclosure, there is provided the use of a pharmaceutical composition as defined herein for use in the manufacture of a medicament for the treatment of pain, such as neuropathic pain, inflammatory pain, acute and chronic nociceptive pain and visceral pain conditions.

[0036] According to a further aspect of the disclosure, there is provided a method of treating pain, such as neuropathic pain, inflammatory pain, acute and chronic nociceptive pain and visceral pain conditions, which comprises administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition as defined herein.

Dosing

Brivaracetam and Levetiracetam Dosing

[0037] In the methods and formulations disclosed herein, brivaracetam or levetiracetam and an opioid are administered.

[0038] The quantity and spacing of dosages of both brivaracetam or levetiracetam and opioids may be determined by the nature and extent of the condition being treated, the form, route and site of administration, and the particular mammal being treated. As described herein, the quantity of opioids administered can depend on variations from initial dose or maintenance dose, FDA suggestions, and morphine equivalents. In addition, factors associated with the particular subject being treated, including subject age, weight, diet and time of administration, will result in the need to adjust dosages. It will also be appreciated by one of skill in the art that the optimal course of treatment, i.e., the number of doses of a compound of the disclosure given per day for a defined number of days, can be ascertained by those skilled in the art using conventional course of treatment determination tests. [0039] In some instances, a dose is administered in comparison to a baseline dose. As is clear from the disclosure, in general, the baseline dose is a dose that the subject has been previously administered over a period of time.

[0040] Where brivaracetam or levetiracetam and opioid are administered in separate dosage forms, the number of dosages administered per day for each compound may be the same or different. Brivaracetam or levetiracetam and opioid may be administered via the same or different routes of administration depending on the compound. Examples of suitable methods of administration include, but are not limited to, oral (i.e. peroral p.o.), intravenous (iv), intramuscular (im), subcutaneous (sc), intranasal, transdermal, and rectal. Compounds may also be administered directly to the nervous system including, but not limited to, intracerebral, intraventricular, intracerebroventhcular, intrathecal, intracisternal, intraspinal and/or peri-spinal routes of administration by delivery via intracranial or intravertebral needles and/or catheters with or without pump devices. Brivaracetam or levetiracetam and opioid may be administered according to simultaneous or alternating regimens, at the same or different times during the course of the therapy, concurrently in divided or single forms.

[0041 ] Brivaracetam or levetiracetam and opioid may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three or four times daily.

[0042] Brivaracetam or levetiracetam and opioid may be administered as a pharmaceutical composition. Pharmaceutical compositions can be prepared by intimately mixing the compounds with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. These procedures may involve mixing, granulating and compressing or dissolving the ingredients as appropriate to the desired preparation.

[0043] Doses provided in the disclosure may be formulated in a unit dosage form. A unit dosage form refers to a physically discrete unit suitable as a unitary dose for individuals undergoing treatment, with each unit containing a predetermined quantity of levetiracetam or brivaracetam calculated to produce an intended therapeutic effect. A unit dosage form may be for a single daily dose, for administration 2 times per day, or one of multiple daily doses, e.g., 3 or more times per day. When multiple daily doses are used, a unit dosage form may be the same or different for each dose. One or more dosage forms may comprise a dose, which may be administered to an individual at a single point in time or during a time interval.

[0044] The amount of a levetiracetam dose can be chosen to any quantity appropriate for a specific treatment. In some variations, the levetiracetam dose can be at least 20 mg, 40 mg, 60 mg, 80 mg, 1 00 mg, 120 mg, 140 mg, 160 mg, 180 mg, and 200 mg. In some variations, the dose can be less than or equal to 300 mg, 280 mg, 260 mg, 240 mg, 220 mg, 200 mg, 180 mg, 160 mg, 140 mg, 120 mg, and 100 mg.

[0045] In some variations, levetiracetam can be administered by intravenous infusion at a daily dose of 1000 mg. The daily dose can be administered as a twice daily 500 mg dose. In some variations, the dose can increase in increments of 1000 mg/day every two weeks to a maximum daily dose of 3000 mg. In some variations, levetiracetam can be administered in 1000 mg once daily doses. In some variations, levetiracetam can be administered in increments of 1000 mg every two weeks to the maximum daily dose of 3000 mg. In some variations, the daily dose of levetiracetam can be administered as an oral solution of 100 mg/ml. In some variations, levetiracetam can be administered as a 250 mg, 500 mg, 750 mg, or 1 gram tablet.

[0046] In some variations, levetiracetam can be administered intrathecally, such as with an infusion pump (e.g., the Medtronic Synchromed II Programmable Infusion Pump). Intrathecal administration can has lower dosing than other dosing methods, and can be delivered continuously, as a bolus, or with varying concentration over a period of time. In some variations, the levetiracetam intrathecal dose can be at least 20 micrograms, 40 micrograms, 60 micrograms, 80 micrograms, 100 micrograms, 120 micrograms, 140 micrograms, 160 micrograms, 180 micrograms, and 200 micrograms. In some variations, the dose can be less than or equal to 300 micrograms, 280 micrograms, 260 micrograms, 240 micrograms, 220 micrograms, 200 micrograms, 180 micrograms, 160 micrograms, 140 micrograms, 120 micrograms, and 100 micrograms.

[0047] In some variations, the brivaracetam dose can be at least 10 mg, 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, or 200 mg. In some variations, the dose can be less than or equal to 300 mg, 275 mg, 250 mg, 225 mg, 200 mg, 175 mg, 150 mg, 125 mg, or 100 mg. In some variations, brivaracetam can be administered as an oral solution of 100 mg/mL. In some variations, Such variations can be by any mode of administration, including intravenous and oral administration. Brivaracetam can be administered as 50 mg PO BID initially. Based on individual tolerability and therapeutic responses, the dose can be adjusted down to 25 mg BID (50 mg/day) or up to 100 mg BID (200 mg/day). Alternatively, brivaracetam can be administered by IV injection. Injection can be at the same dosage and same frequency as tablets or oral solution. In some variations, brivaracetam can be administered intravenously at 50 mg/5mL. In some variations, brivaracetam can be administered by oral tablets at 10 mg, 25 mg, 50 mg, 75 mg, or 100 mg.

[0048] In some variations, brivaracetam can be administered intrathecally. As with intrathecal levetiracetam administration, administration can has lower dosing than other dosing methods, and can be delivered continuously, as a bolus, or with varying concentration over a period of time. In some variations, the brivaracetam dose can be at least 10 micrograms, 25 micrograms, 50 micrograms, 75 micrograms, 100 micrograms, 125 micrograms, 150 micrograms, 175 micrograms, or 200 micrograms. In some variations, the dose can be less than or equal to 300 micrograms, 275 micrograms, 250 micrograms, 225 micrograms, 200 micrograms, 175 micrograms, 150 micrograms, 125 micrograms, or 100 micrograms. [0049] An appropriate dose of levetiracetam or brivaracetam or pharmaceutical composition comprising levetiracetam or brivaracetam may be determined according to any one of several well-established protocols. For example, animal studies such as studies using mice, rats, dogs, and/or monkeys may be used to determine an appropriate dose of a pharmaceutical compound. Results from animal studies may be extrapolated to determine doses for use in other species, such as, for example, humans.

[0050] In some variations, brivaracetam or levetiracetam can be administered as

recommended by FDA guidance.

[0051] Brivaracetam can be administered as an intravenous solution at 10 img/mL, a 10 img/mL oral solution, or as tablets. For tablet or oral solution administration, the recommended starting dosage is 50 mg twice daily. Based on individual patient tolerability and therapeutic response, the dosage may be adjusted down to 25 mg twice daily (50 mg per day) or up to 100 mg twice daily (200 mg per day). When oral administration is not feasible, the same dosage can be administered by intravenous injection. The dosage of brivaracetam can be altered from the approved dosage.

[0052] Levetiracetam can be administered orally at 1000 mg daily as an oral immediate release or oral extended release. Levetiracetam can be administered by intravenous injection when oral administration is not feasible. The dosage of levetiracetam can be altered from the approved dosage.

[0053] Either brivaracetam or levetiracetam can be administered in varying amounts lower or higher than described herein without departing from the disclosure.

Opioid Dosages

[0054] The dose of opioid can depend on the opioid. Specifically, different opioids can be administered in different doses depending on the opioid, mode of administration, and whether the subject is opioid-exposed. The opioid dose of a particular opioid can be determined relative to morphine equivalent. Table 1 depicts conversion of representative opioids in terms of morphine equivalents.

Table 1

Morphine 1 .00

Oxycodone 1 .50

Oxymorphone 3.00

Tapentadol 0.40

Tramadol 0.10

^*Special considerations apply for calculating Methadone dosage.

[0055] Table 2 shows a non-limiting list of representative opioids, with representative conventional dosages for different administration and formulations.

[0056] The combination therapy can be used to reduce the dose of opioid administered to a subject, while retaining the same therapeutic outcome. In some variations, when

brivaracetam or levetiracetam is administered, the initial opioid dose can be reduced by a percentage compared to the recommended dose. For example, the initial opioid dose can be reduced by at least 10% of the conventional initial dose described in Table 2. Other variations are possible. In some variations, the initial opioid dose can be reduced by at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, or at least 80% as compared to the conventional initial dose described in Table 2.

[0057] Likewise, the maintenance dose of opioid can be reduced. In many variations, the maintenance dose of opioid can be reduced by at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, or at least 80% as compared to the conventional initial dose described in Table 2. The reduced dose is relative to morphine as described in Table 1 .

[0058] In some variations, combination therapy that includes a reduced opioid dose results in no increase in pain on a 0-10 pain scale. In some variations, the combination therapy that included a reduced opioid dose results in reduced pain on a 0-10 pain scale. In some instances, the reduced pain is at least 1 . In some instances, the reduced pain is at least 2. In some instances, the reduced pain is at least 3. In some instances, the reduced pain is at least 4, 5, 6, 7, or 8.

[0059] In some variations, the dose of opioid administered can be reduced from the conventionally administered dose by a particular percentage per given time period following the beginning of brivaracetam or levetiracetam administration. In some instances, the opioid dose is reduced by at least 10% per month. In some instances, the dose of opioid is reduced by at least 20% per month. Additional variations are possible. In some further variations, the opioid dose administered to the subject is reduced by at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, or at least 80% per month. In some variations, combination therapy that includes a reduced opioid dose results in no increase in pain on a 0-10 pain scale. [0060] In some variations, such as when a patient is treated for chronic pain, the initial dose of opioid is far above initial and maintenance doses for opioids. In such instances, the reductions in dose of opioid as described herein can be relative to the elevated dose for chronic pain.

[0061] In some variations, the dose of opioid administered is reduced by a particular percentage over a given period of time when brivaracetam or levetiracetam is administered.

[0062] The long term reduced dose of opioid when brivaracetam or levetiracetam is administered can plateau at a particular end point. In some variations, the dose of opioid is reduced by at least 10%. Other reductions in opioid doses are possible. In some variations, the dose of opioid after four, alternatively five, or alternatively six months is reduced by at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90%. In some instances, administration of opioids is stopped.

Table 2

Buprenorphine transmucosal Day 1 : 8 mg 4 to 24 mg/day; dose (for opioid sublingually adjustments may be dependence) once a day made in

Day 2: 16 mg increments/decrements sublingually of 2 or 4 mg to a level once a day that suppresses opioid withdrawal symptoms and holds the patient in treatment.

Buprenorphine deep IM or slow IV 0.3 mg (over at 0.3 mg deep IM or slow (Pain) least 2 minutes) IV at up to 6-hour intervals as needed

Buprenorphine transdermal 7.5 meg, 10

(chronic pain) meg, 15 meg,

and 20 mcg/hr

depending on

prior opioid

dose.

Methadone Oral for chronic Initial dose: 2.5 For patients receiving a pain mg orally every total daily baseline oral

8 to 12 hour morphine equivalent dose < 100 mg:

estimate the daily oral methadone

requirement at 20% to 30%.

-For patients receiving a total daily baseline oral morphine equivalent dose of 100 to 300 mg: estimate the daily oral methadone requirement at 10% to 20%.

-For patients receiving a total daily baseline oral morphine equivalent dose of 300 to 600 mg: estimate the daily oral methadone requirement at 8% to 12%.

-For patients receiving a total daily baseline oral morphine equivalent dose of 600 to 1000 mg: estimate the daily oral methadone

requirement at 5% to 10%.

-For patients receiving a total daily baseline oral morphine equivalent dose greater than 1000 mg: estimate the daily oral methadone

requirement at less than 5%.

-Divide the total daily methadone dose by the number of doses permitted based on dosing interval; always round down, if necessary.

Use a conversion ratio of 2:1 for oral to parenteral (e.g., oral methadone 10 mg to parenteral methadone 5 mg) Morphine Immediate 15 to 30 mg

release tablets: orally every 4

hours as

needed

Oral solution: 10 to 20 mg

orally every 4

hours as

needed

Extended-release

oral:

Suppository 10 to 20 mg rectally every 4 hours needed

Subcutaneous/I M: 10 mg every 4 5 to 20 mg every 4 hours as hours as needed needed

IV 4 to 10 mg Dose range: 5 to 15 mg every 4 hours Daily dose range: 12 to administered 120 mg

slowly over 4 to Alternate dose: 2 to 10

5 minutes mg/70 kg of body

weight

Epidural 5 mg in the incremental doses of 1 lumbar region to 2 mg at intervals

Intrathecal 0.2 to 1 mg Not recommended

Naltrexone oral tablets 50 mg once per day extended release 380 mg every 4 injectable weeks/month suspension

Nalbuphine IV, IM, or 10 mg/70 kg

subcutaneous administered every 3 to

6 hours as needed

Oxycodone immediate in opioid-naive

release oral subjects is 5 to

solution 15 mg orally

every 4 to 6

hours

extended release tablets (e.g., 10 mg formulation orally every 12 hours capsules (e.g., 9 mg orally every 12 hours) oral solution are restricted to oxycodone tolerant subjects (e.g., oral morphine 60 mg/day; transdermal fentanyl 25 mcg/hr; oral oxycodone 30 mg/day; oral hydromorphone 8 mg/day; oral oxymorphone 25 mg/day or an equianalgesic dose of another opioid. Oxymorphone titrated to the 10 to 20 mg

desired level of every 4 to 6

analgesia hours

Tramadol Oral 25 mg daily 50 - 100 mg 4x daily

(immediate

release)

Tramadol Oral 100 mg orally 300 mg

(extended once a day

release)

2-Oxo-l -Pyrrolidine Derivatives

[0063] In further aspects, a 2-oxo-1 -pyrrolidine derivative of brivaracetam or levetiracetam may be used instead of brivaracetam or levetiracetam.

[0064] In one aspect, the disclosure therefore provides a compound having the formula (I) a pharmaceutically acceptable salt thereof

wherein

X is— CA¹NR⁵R⁶ or— CA¹OR⁷ or— CA¹-R⁸ or CN;

A¹ and A² are independently oxygen, sulfur or— NR⁹;

R¹ is hydrogen, alkyl, aryl or— CH₂— R^1awherein R^1a is aryl, heterocycle, halogen, hydroxy, amino, nitro or cyano;

R², R³ and R⁴ are the same or different and each is independently hydrogen, halogen, hydroxy, thiol, amino, nitro, nitrooxy, cyano, azido, carboxy, amido, sulfonic acid, sulfonamide, alkyl, alkenyl, alkynyl, ester, ether, aryl, heterocycle, or an oxy derivative, thio derivative, amino derivative, acyl derivative, sulfonyl derivative or sulfinyl derivative;

R^2a, R^3a and R^4aare the same or different and each is independently hydrogen, halogen, alkyl, alkenyl, alkynyl or aryl;

R⁵, R⁶, R⁷ and R⁹ are the same or different and each is independently hydrogen, hydroxy, alkyl, aryl, heterocycle or an oxy derivative; and

R⁸ is hydrogen, hydroxy, thiol, halogen, alkyl, aryl, heterocycle or a thio derivative.

[0065] In some aspects, at least one of as R², R³, R⁴, R^2a, R^3a and R^4a is other than hydrogen. [0066] In some aspects, when the compound is a mixture of all possible isomers, X is

— CONR⁵R⁶, A² is oxygen, and R¹ is hydrogen, methyl, ethyl or propyl then substitution on the pyrolidine ring is other than mono-, di-, or tri-methyl or mono-ethyl.

[0067] In some aspects, when R¹, R², R⁴, R^2a, R^3a and R^4a are each hydrogen, A² is oxygen, and X is CONR⁵R⁶, then R³is different from carboxy, ester, amido, substituted oxo-pyrrolidine, hydroxy, oxy derivative, amino, amino derivatives, methyl, naphthyl, phenyl optionally substituted by oxy derivatives or in the para position by an halogen atom.

[0068] In the definitions set forth herein, unless otherwise stated, R¹¹ and R¹² are the same or different and each is independently amido, alkyl, alkenyl, alkynyl, acyl, ester, ether, aryl, aralkyl, heterocycle or an oxy derivative, thio derivative, acyl derivative, amino derivative, sulfonyl derivative, or sulfinyl derivative, each optionally substituted with any suitable group, including, but not limited to, one or more moieties selected from lower alkyl or other groups as described below as substituents for alkyl.

[0069] The term "oxy derivative", as used herein is defined as including— O— R¹¹ groups wherein R¹¹ is as defined above except for "oxy derivative". Non-limiting examples are alkoxy, alkenyloxy, alkynyloxy, acyloxy, oxyester, oxyamido, alkylsulfonyloxy, alkylsulfinyloxy, arylsulfonyloxy, arylsulfinyloxy, aryloxy, aralkoxy or heterocyclooxy such as pentyloxy, allyloxy, methoxy, ethoxy, phenoxy, benzyloxy, 2-naphthyloxy, 2-pyridyloxy, methylenedioxy, and carbonate.

[0070] The term "thio derivative" as used herein, is defined as including— S— R¹¹ groups wherein R¹¹ is as defined above except for "thio derivative". Non-limiting examples are alkylthio, alkenylthio, alkynylthio and arylthio.

[0071] The term "amino derivative" as used herein, is defined as including— NHR¹¹ or

— NR¹¹R¹² groups wherein R¹¹ and R¹² are as defined above. Non-limiting examples are mono- or di-alkyl-, alkenyl-, alkynyl- and arylamino or mixed amino.

[0072] The term "acyl derivative" as used herein, represents a radical derived from carboxylic acid and thus is defined as including groups of the formula R¹¹— CO— , wherein R¹¹ is as defined above and may also be hydrogen. Non-limiting examples are formyl, acetyl, propionyl, isobutyryl, valeryl, lauroyl, heptanedioyl, cyclohexanecarbonyl, crotonoyl, fumaroyl, acryloyl, benzoyl, naphthoyl, furoyl, nicotinoyl, 4-carboxybutanoyl, oxalyl, ethoxalyl, cysteinyl, oxamoyl.

[0073] The term "sulfonyl derivative" as used herein, is defined as including a group of the formula— S0₂— R¹¹, wherein R¹¹ is as defined above except for "sulfonyl derivative".

Non-limiting examples are alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl and arylsulfonyl.

[0074] The term "sulfinyl derivative" as used herein, is defined as including a group of the formula— SO— R¹¹, wherein R¹¹ is as defined above except for "sulfinyl derivative".

Non-limiting examples are alkylsulfinyl, alkenylsulfinyl, alkynylsulfinyl and arylsulfinyl. [0075] The term "alkyl", as used herein, is defined as including saturated, monovalent hydrocarbon radicals having straight, branched or cyclic moieties or combinations thereof and containing 1 -20 carbon atoms, alternatively 1 -6 carbon atoms for non-cyclic alkyl and 3-6 carbon atoms for cycloalkyl (in these two cases, unless otherwise specified, "lower alkyl"). Alkyl moieties may optionally be substituted by 1 to 5 substituents independently selected from the group consisting of halogen, hydroxy, thiol, amino, nitro, cyano, thiocyanato, acyl, acyloxy, sulfonyl derivative, sulfinyl derivative, alkylamino, carboxy, ester, ether, amido, azido, cycloalkyl, sulfonic acid, sulfonamide, thio derivative, oxyester, oxyamido, heterocycle, vinyl, C1 -5-alkoxy, C₆-io-aryloxy and C₆-io-aryl.

[0076] In some variations, alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, iso or ter-butyl, and 2,2,2-trimethylethyl each optionally substituted by at least one substituent selected from the group consisting of halogen, hydroxy, thiol, amino, nitro and cyano, such as trifluoromethyl, trichloromethyl, 2,2,2-trichloroethyl, 1 ,1 -dimethyl-2,2-dibromoethyl, and 1 ,1 -dimethyl-2,2,2-trichloroethyl.

[0077] The term "alkenyl" as used herein, is defined as including both branched and unbranched, unsaturated hydrocarbon radicals having at least one double bond such as ethenyl (=vinyl), 1 -methyl-1 -ethenyl, 2,2-dimethyl-1 -ethenyl, 1 -propenyl, 2-propenyl (=allyl), 1 -butenyl, 2-butenyl, 3-butenyl, 4-pentenyl, 1 -methyl-4-pentenyl, 3-methyl-1 -pentenyl, 1 -hexenyl, 2-hexenyl, and the like and being optionally substituted by at least one substituent selected from the group consisting of halogen, hydroxy, thiol, amino, nitro, cyano, aryl and heterocycle such as mono- and di-halo vinyl where halo is fluoro, chloro or bromo.

[0078] The term "alkynyl" as used herein, is defined as including a monovalent branched or unbranched hydrocarbon radical containing at least one carbon-carbon triple bond, for example ethynyl, 2-propynyl (=propargyl), and the like and being optionally substituted by at least one substituent selected from the group consisting of halogen, hydroxy, thiol, amino, nitro, cyano, aryl and heterocycle, such as haloethynyl.

[0079] When as bridging groups, alkyl, alkenyl and alkynyl represent straight- or branched chains, C1 -12, alternatively C1 -4-alkylene or C2-12-, alternatively C2-4-alkenylene or -alkynylene moieties respectively.

[0080] Groups where branched derivatives are conventionally qualified by prefixes such as "n", "sec", "iso" and the like (e.g. "n-propyl", "sec-butyl") are in the n-form unless otherwise stated.

[0081] The term "aryl" as used herein, is defined as including an organic radical derived from an aromatic hydrocarbon consisting of 1 -3 rings and containing 6-30 carbon atoms by removal of one hydrogen, such as phenyl and naphthyl each optionally substituted by 1 to 5 substituents independently selected from halogen, hydroxy, thiol, amino, nitro, cyano, acyl, acyloxy, sulfonyl, sulfinyl, alkylamino, carboxy, ester, ether, amido, azido, sulfonic acid, sulfonamide, alkylsulfonyl, alkylsulfinyl, alkylthio, oxyester, oxyamido, aryl, C1 -6-alkoxy,

C6-10-aryloxy, C1 -6-alkyl, and C1 -6-haloalkyl. Aryl radicals are alternatively monocyclic containing 6-10 carbon atoms. Aryl groups are phenyl and naphthyl each optionally substituted by 1 to 5 substituents independently selected from halogen, nitro, amino, azido, C1 -6-alkoxy, C1 -6-alkylthio, C1 -6-alkyl, C1 -6-haloalkyl and phenyl.

[0082] The term "halogen", as used herein, includes an atom of CI, Br, F, I.

[0083] The term "hydroxy", as used herein, represents a group of the formula— OH.

[0084] The term "thiol", as used herein, represents a group of the formula— SH.

[0085] The term "cyano", as used herein, represents a group of the formula— CN.

[0086] The term "nitro", as used herein, represents a group of the formula— N0₂.

[0087] The term "nitrooxy", as used herein, represents a group of the formula— ON0₂.

[0088] The term "amino", as used herein, represents a group of the formula— NH₂.

[0089] The term "azido", as used herein, represents a group of the formula— N₃.

[0090] The term "carboxy", as used herein, represents a group of the formula— COOH.

[0091] The term "sulfonic acid", as used herein, represents a group of the formula— S0₃H.

[0092] The term "sulfonamide", as used herein, represents a group of the formula— S0₂NH₂.

[0093] The term "ester" as used herein is defined as including a group of formula

— COO— R¹¹wherein R¹¹ is as defined above except oxy derivative, thio derivative or amino derivative.

[0094] The term "ether" is defined as including a group selected from C1 -50-straight or branched alkyl, or C2-50-straight or branched alkenyl or alkynyl groups or a combination of the same, interrupted by one or more oxygen atoms.

[0095] The term "amido" is defined as including a group of formula— CONH₂ or— CONHR¹¹or —CONR¹¹R¹² wherein R¹¹ and R¹² are as defined above.

[0096] The term "heterocycle", as used herein is defined as including an aromatic or non aromatic cyclic alkyl, alkenyl, or alkynyl moiety as defined above, having at least one O, S and/or N atom interrupting the carbocyclic ring structure and optionally, one of the carbon of the carbocyclic ring structure may be replaced by a carbonyl. Non-limiting examples of aromatic heterocycles are pyridyl, furyl, pyrrolyl, thienyl, isothiazolyl, imidazolyl,

benzimidazolyl, tetrazolyl, quinazolinyl, quinolizinyl, naphthyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinolyl, isoquinolyl, isobenzofuranyl, benzothienyl, pyrazolyl, indolyl, indolizinyl, purinyl, isoindolyl, carbazolyl, thiazolyl, 1 ,2,4-thiadiazolyl, thieno(2,3-b)furanyl, furopyranyl, benzofuranyl, benzoxepinyl, isooxazolyl, oxazolyl, thianthrenyl, benzothiazolyl, or benzoxazolyl, cinnolinyl, phthalazinyl, quinoxalinyl, phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl, phenothiazinyl, furazanyl, isochromanyl, indolinyl, xanthenyl, hypoxanthinyl, pteridinyl, 5-azacytidinyl, 5-azauracilyl, triazolopyridinyl, imidazolopyridinyl, pyrrolopyrimidinyl, and pyrazolopyrimidinyl optionally substituted by alkyl or as described above for the alkyl groups. Non-limiting examples of non aromatic heterocycles are tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperidyl, piperazinyl, imidazolidinyl, morpholino, morpholinyl, 1 -oxaspiro(4.5)dec-2-yl, pyrrolidinyl, 2-oxo-pyrrolidinyl, sugar moieties (i.e. glucose, pentose, hexose, ribose, fructose, which may also be substituted) or the same which can optionally be substituted with any suitable group, including but not limited to one or more moieties selected from lower alkyl, or other groups as described above for the alkyl groups. The term

"heterocycle" also includes bicyclic, tricyclic and tetracyclic, spiro groups in which any of the above heterocyclic rings is fused to one or two rings independently selected from an aryl ring, a cyclohexane ring, a cyclohexene ring, a cyclopentane ring, a cyclopentene ring or another monocyclic heterocyclic ring or where a monocyclic heterocyclic group is bridged by an alkylene group, such as quinuclidinyl, 7-azabicyclo(2.2.1 )heptanyl,

7-oxabicyclo(2.2.1 )heptanyl, and 8-azabicyclo(3.2.1 )octanyl.

[0097] In the above definitions it is to be understood that when a substituent such as R², R³, R⁴, R^2a, R^3a, R^4a, R⁵, R⁶, R⁷, R⁸ is attached to the rest of the molecule via a heteroatom or a carbonyl, a straight- or branched chain, C1 -12-, alternatively C1 -4-alkylene or C2-12, alternatively C2-4-alkenylene or -alkynylene bridge may optionally be interposed between the heteroatom or the carbonyl and the point of attachment to the rest of the molecule.

[0098] Some examples of X are—COO R⁷ or— CONR⁵R⁶, wherein R⁵, R⁶ and R⁷ are alternatively hydrogen, C1 -4-alkyl, phenyl or alkylphenyl.

[0099] Alternatively X is carboxy or— CONR⁵R⁶, wherein R⁵ and R⁶ are alternatively hydrogen, C1 -4-alkyl, phenyl or alkylphenyl, especially— CONH₂.

[00100] Alternatively A¹ and A² are each oxygen.

[00101] Alternatively R¹ is hydrogen, alkyl, especially C1 -12 alkyl, particularly lower alkyl or aryl especially phenyl.

[00102] Examples of R¹ groups are methyl, ethyl, propyl, isopropyl, butyl, iso- or ter-butyl, 2,2,2-trimethylethyl each optionally attached via a methylene bridge or the same substituted by at least one halogen atom such as trifluoromethyl, trichloromethyl,

2,2,2-trichloroethyl, 1 ,1 -dimethyl-2,2-dibromoethyl, 1 ,1 -dimethyl-2,2,2-trichloroethyl. In some instances, R¹ is ethyl.

[00103] R² and R^2a are independently hydrogen, halogen or alkyl, especially lower alkyl.

[00104] Examples of R² and R^2a groups are independently hydrogen, halogen or methyl, ethyl, propyl, isopropyl, butyl, iso or ter-butyl, 2,2,2-trimethylethyl or the same substituted by at least one halogen atom such as trifluoromethyl, trichloromethyl,

2,2,2-trichloroethyl, 1 ,1 -dimethyl-2,2-dibromoethyl, and 1 ,1 -dimethyl-2,2,2-trichloroethyl.

[00105] Especially at least one and alternatively both of R² and R^2a are hydrogen.

[00106] Alternatively R^3a, R⁴ and R^4a are independently hydrogen, alkyl, especially methyl or ethyl or aryl especially phenyl or aralkyl, especially benzyl. [00107] Examples of R^3a, R⁴ and R^4a groups are independently hydrogen, halogen or methyl, ethyl, propyl, isopropyl, butyl, iso or ter-butyl, 2,2,2-trimethylethyl or the same substituted by at least one halogen atom such as trifluoromethyl, trichloromethyl,

2,2,2-trichloroethyl, 1 ,1 -dimethyl-2,2-dibromoethyl, and 1 ,1 -dimethyl-2,2,2-trichloroethyl.

[00108] Especially at least one and alternatively both of R⁴ and R^4a are hydrogen.

[00109] R^3a is particularly hydrogen or alkyl, especially lower alkyl and is alternatively hydrogen.

[00110] Alternatively R³ is hydrogen, C1 -12-alkyl, especially C1 -6-alkyl, each optionally substituted by one or more substituents selected from hydroxy, halogen, cyano, thiocyanato or alkoxy and attached to the ring either directly or via a thio, sulfonyl, sulfonyl, carbonyl or oxycarbonyl group and optionally, a C1 -4-alkylene bridge, particularly methylene;

C2-6-alkenyl or -alkynyl, especially C2-3-alkenyl or -alkynyl each optionally substituted by one or more halogens; azido; cyano; amido; carboxy; triazolyl, tetrazolyl, pyrrolidinyl, pyridyl, 1 -oxidopyridyl, thiomorpholinyl, benzodioxolyl, furyl, oxazolyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl or piperazinyl each optionally substituted by one or more substituents selected from halogen, C1 -6-alkyl and phenyl and attached to the ring either directly or via a carbonyl group or a C1 -4-alkylene bridge, particularly methylene; naphthyl; or phenyl, phenylalkyl or phenylalkenyl each optionally substituted by one or more substituents selected from halogen, C1 -6-alkyl, C1 -6 haloalkyl, C1 -6-alkoxy, C1 -6-alkylthio, amino, azido, phenyl and nitro and each attached to the ring either directly or via an oxy, sulfonyl, sulfonyloxy, carbonyl or carbonyloxy group and optionally additionally a C1 -4-alkylene bridge, particularly methylene.

[00111 ] Also, preferably, R³ is C1 -6-alkyl optionally substituted by one or more substituents selected from halogen, thiocyanato, azido, alkoxy, alkylthio, phenylsulfonyl; nitrooxy; C2-3-alkenyl or -alkynyl each optionally substituted by one or more halogens or by acetyl; tetrazolyl, pyridyl, furyl, pyrrolyl, thiazolyl or thienyl; or phenyl or phenylalkyl each optionally substituted by one or more substituents selected from halogen, C1 -6-alkyl, C1 -6 haloalkyl, C1 -6-alkoxy, amino, azido, phenyl and nitro and each attached to the ring either directly or via a sulfonyloxy and optionally additionally a C1 -4-alkylene bridge, particularly methylene.

[00112] Other examples of R³ groups are hydrogen, halogen or methyl, ethyl, propyl, isopropyl, butyl, iso or ter-butyl, 2,2,2-trimethylethyl or the same substituted by at least one halogen atom such as trifluoromethyl, trichloromethyl, 2,2,2-trichloroethyl,

1 , 1 -dimethyl-2,2-dibromoethyl, 1 ,1 -dimethyl-2,2,2-trichloroethyl.

[00113] R³ is especially C1 -4-alkyl optionally substituted by one or more substituents selected from halogen, thiocyanato or azido; C2-5-alkenyl or -alkynyl, each optionally substituted by one or more halogens; thienyl; or phenyl optionally substituted by one or more substituents selected from halogen, C1 -6-alkyl, C1 -6 haloalkyl or azido.

[00114] Further examples of R³ groups are C1 -6 alkyl and C2-6 haloalkenyl.

[00115] Alternatively R⁵ and R⁶ are independently hydrogen, methyl, ethyl, propyl, isopropyl, butyl, iso or ter-butyl, 2,2,2-trimethylethyl, especially hydrogen or methyl.

[00116] Especially at least one and alternatively both of R⁵ and R⁶ are hydrogen.

[00117] Alternatively R⁷ is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, iso or tert-butyl, 2,2,2-trimethylethyl, methoxy, ethoxy, phenyl, benzyl or the same substituted by at least one halogen atom such as trifluoromethyl, chlorophenyl.

[00118] Alternatively R⁷ is hydrogen, methyl or ethyl especially hydrogen.

[00119] Alternatively R⁸ is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, iso or ter-butyl, 2,2,2-trimethylethyl, phenyl, benzyl or the same substituted by at least one halogen atom such as trifluoromethyl, chlorobenzyl.

[00120] Alternatively R⁸ is hydrogen or methyl.

[00121 ] A particular group of compounds of formula I (Compounds 1 A) comprises those wherein,

[00122] A2 is oxygen;

[00123] X is— CONR⁵R⁶ or— COOR⁷ or— CO— R⁸ or CN;

[00124] R¹ is hydrogen or alkyl, aryl, halogen, hydroxy, amino, nitro, cyano;

[00125] R², R³, R⁴, are the same or different and each is independently hydrogen or halogen, hydroxy, amino, nitro, cyano, acyl, acyloxy, a sulfonyl derivative, a sulfinyl derivative, an amino derivative, carboxy, ester, ether, amido, sulfonic acid, sulfonamide, alkoxycarbonyl, a thio derivative, alkyl, alkoxy, oxyester, oxyamido, aryl, an oxy derivative, heterocycle, vinyl and R³ may additionally represent C2-5 alkenyl, C2-5 alkynyl or azido each optionally substituted by one or more halogen, cyano, thiocyano, azido, cyclopropyl, acyl and/or phenyl; or phenylsulfonyloxy whereby any phenyl moiety may be substituted by one or more halogen, alkyl, haloalkyl, alkoxy, nitro, amino, and/or phenyl; alternatively methyl, ethyl, propyl, isopropyl, butyl, or isobutyl.

[00126] R^2a, R^3a and R^4a are hydrogen

[00127] R⁵, R⁶, R⁷ are the same or different and each is independently hydrogen, hydroxy, alkyl, aryl, heterocycle or oxy derivative; and

[00128] R⁸ is hydrogen, hydroxy, thiol, halogen, alkyl, aryl, heterocycle, alkylthio or thio derivative.

[00129] Within these Compounds 1 A, R¹ is alternatively methyl, ethyl, propyl, isopropyl, butyl, or isobutyl; alternatively methyl, ethyl or n-propyl.

[00130] R² and R⁴ are alternatively independently hydrogen or halogen or methyl, ethyl, propyl, isopropyl, butyl, isobutyl ; and, alternatively, are each hydrogen. [00131 ] R³ is alternatively C1 -5 alkyl, C2-5 alkenyl, C2-C5 alkynyl, cyclopropyl, azido, each optionally substituted by one or more halogen, cyano, thiocyano, azido, alkylthio, cyclopropyl, acyl and/or phenyl ; phenyl; phenylsulfonyl; phenylsulfonyloxy, tetrazole, thiazole, thienyl, furyl, pyrrole, pyridine, whereby any phenyl moiety may be substituted by one or more halogen, alkyl, haloalkyl, alkoxy, nitro, amino, and/or phenyl ; alternatively methyl, ethyl, propyl, isopropyl, butyl, or isobutyl.

[00132] X is alternatively— COOH or— COOMe or— COOEt or— CONH₂; alternatively — CONH₂.

[00133] A further particular group of compounds of formula I (Compounds 1 B) comprises those wherein,

[00134] X is— CA¹NH₂,— CA¹NHCH₃ or— CA¹N(CH₃)₂;

[00135] R¹ is alkyl or phenyl;

[00136] R³ is alkyl, alkenyl, alkynyl, cyano, isothiocyanato, ether, carboxyl, amido, aryl, heterocycle; or

[00137] R³ is CH₂R¹⁰ wherein R¹⁰ is hydrogen, cycloalkyl, oxyester, oxyalkylsulfonyl, oxyarylsufonyl, aminoalkylsulfonyl, aminoarylsulfonyl, nitrooxy, cyano, isothiocyanato, azido, alkylthio, arylthio, alkylsulfinyl, alkylsulfonyl, heterocycle, aryloxy, alkoxy or trifluoroethyl;

[00138] R^3a is hydrogen, alkyl or aryl (especially with the proviso that when R^3a is hydrogen, R³other than methyl);

[00139] or R³R^3a form a cycloalkyl;

[00140] and R², R^2a, R⁴ and R^4a are each hydrogen.

[00141 ] Within the compounds of formula I,

[00142] R¹ is alternatively alkyl especially C1 -12- more particularly C1 -6-alkyl and is alternatively ethyl ;

[00143] R², R^2a, R^3a and R^4a are alternatively hydrogen;

[00144] R³ is alternatively selected from hydrogen ; C1 -12-alkyl, especially C1 -6-alkyl, each optionally substituted by one or more substituents selected from hydroxy, halogen, cyano, thiocyanato or alkoxy and attached to the ring either directly or via a thio, sulfinyl, sulfonyl, carbonyl or oxycarbonyl group and optionally additionally a C1 -4-alkylene bridge, particularly methylene; C2-6-alkenyl or -alkynyl, especially C2-3-alkenyl or -alkynyl, each optionally substituted by one or more halogens; azido; cyano; amido; carboxy; triazolyl, tetrazolyl, pyrrolidinyl, pyridyl, 1 -oxidopyridyl, thiomorpholinyl, benzodioxolyl, furyl, oxazolyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl or piperazinyl each optionally substituted by one or more substituents selected from halogen, C1 -6-alkyl and phenyl and attached to the ring either directly or via a carbonyl group or a C1 -4-alkylene bridge, particularly methylene; naphthyl ; or phenyl, phenylalkyl or phenylalkenyl each optionally substituted by one or more substituents selected from halogen, C1 -6-alkyl, C1 -6 haloalkyl, C1 -6-alkoxy, C1 -6-alkylthio, amino, azido, phenyl and nitro and each attached to the ring either directly or via an oxy, sulfonyl, sulfonyloxy, carbonyl or carbonyloxy group and optionally additionally a

C1 -4-alkylene bridge, particularly methylene;

[00145] R^3a is alternatively hydrogen or C1 -4-alkyl;

[00146] Alternatively R⁴ and R^4aare independently hydrogen, C1 -4-alkyl, phenyl or benzyl.

[00147] A further group of compounds of formula I (Compounds 1 C) comprises those in racemic form wherein, when X is— CONR⁵R⁶ and R¹ is hydrogen, methyl, ethyl or propyl, then substitution on the pyrrolidine ring is other than mono-, di-, or tri-methyl or mono-ethyl.

[00148] A further group of compound of formula I (Compounds 1 D) comprises those in racemic form wherein, when X is— CONR⁵R⁶ and R¹ is hydrogen or C1 -6-alkyl, C2-6-alkenyl or -alkynyl or cycloalkyi, each unsubstituted, then substitution in the ring is other than by alkyl, alkenyl or alkynyl, each unsubstituted.

[00149] A further particular group of compounds of formula I (Compounds 1 E) comprises those wherein,

X is— CA¹NH₂;

R¹ is H;

R³ is azidomethyl, iodomethyl, ethyl optionally substituted by 1 to 5 halogen atoms, n-propyl optionally substituted by 1 to 5 halogen atoms, vinyl optionally substituted by one or two methyl, and/or 1 to 3 halogen atoms, acetylene optionally substituted by C1 -4-alkyl, phenyl or halogen;

R^3a is hydrogen or halogen, alternatively fluorine;

and R², R^2a, R⁴ and R^4aare each hydrogen;

as their racemates or in enantiomerically enriched form, alternatively the pure enantiomers.

[00150] A further particular group of compounds of formula I (Compounds 1 F) comprises those wherein,

X is— CA¹NH₂;

R¹ is H;

R³ is C1 -6-alkyl, C2-6-alkenyl or C2-6-alkynyl optionally substituted by azido, oxynitro,

1 to 6 halogen atoms;

R^3a is hydrogen or halogen, alternatively fluorine;

and R², R^2a, R⁴ and R^4aare each hydrogen;

as their racemates or in enantiomerically enriched form, alternatively the pure enantiomers.

[00151] In all the above mentioned scopes when the carbon atom to which R¹ is attached is asymmetric it is alternatively in the "S"-configuration. [00152] The "pharmaceutically acceptable salts" according to the disclosure include therapeutically active, non-toxic base and acid salt forms which the compounds of formula I are able to form.

[00153] The acid addition salt form of a compound of formula I that occurs in its free form as a base can be obtained by treating the free base with an appropriate acid such as an inorganic acid, for example, a hydrohalic such as hydrochloric or hydrobromic, sulfuric, nitric, phosphoric and the like; or an organic acid, such as, for example, acetic, hydroxyacetic, propanoic, lactic, pyruvic, malonic, succinic, maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic, p-aminosalicylic, pamoic and the like.

[00154] The compounds of formula I containing acidic protons may be converted into their therapeutically active, non-toxic base addition salt forms, e.g. metal or amine salts, by treatment with appropriate organic and inorganic bases. Appropriate base salt forms include, for example, ammonium salts, alkali and earth alkaline metal salts, e.g. lithium, sodium, potassium, magnesium, calcium salts and the like, salts with organic bases, e.g.

N-methyl-D-glucamine, hydrabamine salts, and salts with amino acids such as, for example, arginine, lysine and the like.

[00155] Conversely said salt forms can be converted into the free forms by treatment with an appropriate base or acid.

[00156] Compounds of the formula I and their salts can be in the form of a solvate, which is included within the scope of the disclosure. Such solvates include for example hydrates, alcoholates and the like.

[00157] Many of the compounds of formula I and some of their intermediates have at least one stereogenic center in their structure. This stereogenic center may be present in a R or a S con.uration, said R and S notation is used in correspondance with the rules described in Pure Appl. Chem., 45 (1976) 1 1 -30.

[00158] The disclosure also relates to all stereoisomeric forms such as enantiomeric and diastereoisomeric forms of the compounds of formula I or mixtures thereof (including all possible mixtures of stereoisomers).

[00159] Furthermore certain compounds of formula I which contain alkenyl groups may exist as Z (zusammen) or E (entgegen) isomers. In each instance, the disclosure includes both mixture and separate individual isomers.

[00160] Multiple substituents on the pyrrolidone ring can also stand in either cis or trans relationship to each other with respect to the plane of the pyrrolidone ring.

[00161] Some of the compounds of formula I may also exist in tautomeric forms. Such forms although not explicity indicated in the above formula are intended to be included within the scope of the disclosure. [00162] With respect to the disclosure reference to a compound or compounds is intended to encompass that compound in each of its possible isomeric forms and mixtures thereof unless the particular isomeric form is referred to specifically.

[00163] The disclosure also includes within its scope pro-drug forms of the compounds of formula I and its various sub-scopes and sub-groups.

[00164] The term "prodrug" as used herein includes compound forms which are rapidly transformed in vivo to the parent compound according to the disclosure, for example, by hydrolysis in blood. Prodrugs are compounds bearing groups which are removed by biotransformation prior to exhibiting their pharmacological action. Such groups include moieties which are readily cleaved in vivo from the compound bearing it, which compound after cleavage remains or becomes pharmacologically active. Metabolically cleavable groups form a class of groups well known to practitioners of the art. They include, but are not limited to such groups as alkanoyl (i.e. acetyl, propionyl, butyryl, and the like), unsubstituted and substituted carbocyclic aroyl (such as benzoyl, substituted benzoyl and 1 - and 2-naphthoyl), alkoxycarbonyl (such as ethoxycarbonyl), trialklysilyl (such as trimethyl- and triethylsilyl), monoesters formed with dicarboxylic acids (such as succinyl), phosphate, sulfate, sulfonate, sulfonyl, sulfinyl and the like. The compounds bearing the metabolically cleavable groups have the advantage that they may exhibit improved bioavailability as a result of enhanced solubility and/or rate of absorption conferred upon the parent compound by virtue of the presence of the metabolically cleavable group. T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery System", Vol. 14 of the A.C.S. Symposium Series; "Bioreversible Carriers in Drug Design", ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987. EXAMPLE

[00165] A patient was treated with a combination of opioid and brivaracetam. The patient voluntarily lowered the opioid dose, which was also more effective at a lower dose. The patient further had increased opioid efficacy with absence of withdrawal symptoms. The combination therapy demonstrated the effectiveness of combination therapy as well as the effectiveness of brivaracetam in opioid withdrawal.

[00166] A male subject was administered baclofen 120 mg/day for spacicity,, Cymbalta 120 mg/day and Lyrica 600 mg/day for neuropathic pain, and oxycontin (oxycodone HCI) 180mg/day plus oxycodone 40mg/day for breakthrough pain.

[00167] The patient additionally began a course of brivaracetam at 25mg once a day (qD) for two weeks. This was increased to 50mg/day BID, i.e. 10Omg/day and has remained at this dose for a six month period. [00168] By one to two months after the initial brivaracetam administration, the subject voluntarily decreased his breakthrough dosing of oxycodone to 20 mg/day. Pain decreases from 9-10 (near suicidal) to a solid 6, without severe episodes. By 4-5 months his breakthrough dosing continued to decrease to at times not needing it at all.

[00169] By five months, the breakthrough dose was completely eliminated and replaced with Embeda 100-4 (100 mg morphine plus 4 mg naltrexone) BID. Because oxycodone is 1 .5 times more potent than morphine, the change from 330mg morphine/day as chronic baseline dosing to 200 mg morphine/day, represented a 40% decrease in daily narcotic load, coupled with a substantial decrease in pain from 10 to 6.

[00170] In net, the patient decreased his opioid load, i.e., Oxycontin 180mg qDay plus Oxycodone 40 mg qDay (a 440mg Morphine equivalent) to 32mg Hydromophorne qDay (160 mg Morphine qDay equivalent), representing a 64% reduction of opioid on a regimen of 75mg BID Briviact with pain relief down to 3 out of 10, thus a 70% reduction of pain.

[00171] Having described several embodiments, it will be recognized by those skilled in the art that various modifications, alternative constructions, and equivalents may be used without departing from the spirit of the disclosure. Additionally, a number of well-known processes and elements have not been described in order to avoid unnecessarily obscuring the disclosure. Accordingly, the above description should not be taken as limiting the scope of the disclosure.

[00172] Those skilled in the art will appreciate that the disclosed embodiments teach by way of example and not by limitation. Therefore, the matter contained in the above description or shown in the accompanying drawings should be interpreted as illustrative and not in a limiting sense. The following claims are intended to cover all generic and specific features described herein, as well as all statements of the scope of the method and system, which, as a matter of language, might be said to fall there-between.

Claims

1 . A method of reducing opioid dose without increasing pain to a subject in need thereof, the method comprising:

administering to the subject a combination therapy comprising:

brivaracetam or levetiracetam, and

an opioid at a dose at least 10% lower than the baseline dose in the absence of brivaracetam or levetiracetam,

wherein the subject has no increase in pain on a 0-10 pain scale.

2. The method of claim 1 , comprising administering the opioid at a dose at least 20% lower than the baseline does in the absence of brivaracetam or levetiracetam.

3. The method of claim 1 , comprising administering the opioid at a dose at least 30% lower than the baseline does in the absence of brivaracetam or levetiracetam.

4. The method of any one preceding claim, wherein the subject has a decrease in pain of at least 1 on a 0-10 pain scale.

5. The method of any one preceding claim, wherein the subject has a decrease in pain of at least 3 on a 0-10 pain scale.

6. The method of claim 1 , further comprising reducing the opioid dose by an at least 20% per month.

7. The method of any one preceding claim, wherein brivaracetam is administered.

8. The method of any one of any one of claims 1 -6, wherein levetiracetam is

administered.

9. The method of any one preceding claim, wherein the opioid is selected from Codeine, Fentanyl, Hydrocodone, Hydromorphone, Methadone, Oxycodone, Oxymorphone,

Buprenorphine, Methadone, Morphine, Naltrexone, Nalbuphine, Tramadol, and Tramadol.

10. A method of treating pain in a subject comprising:

administering to the subject a combination therapy comprising:

brivaracetam or levetiracetam, and an opioid;

subsequently, administering to the subject a combination therapy comprising brivaracetam or levetiracetam and the opioid at a maintenance dose at least 10% lower than the dose administered to the subject in the absence of brivaracetam or levetiracetam;

wherein the subject has no increase in pain on a 0-10 pain scale.

1 1. The method of claim 10, comprising administering the opioid at a dose at least 20% lower than the baseline does in the absence of brivaracetam or levetiracetam.

12. The method of claim 10, comprising administering the opioid at a dose at least 30% lower than the baseline does in the absence of brivaracetam or levetiracetam.

13. The method of any one of claims 10-12, wherein the subject has a decrease in pain of at least 1 on a 0-10 pain scale.

14. The method of any one of claims 10-13, wherein the subject has a decrease in pain of at least 3 on a 0-10 pain scale.

15. The method of claim 10, further comprising reducing the opioid dose by an at least 20% per month.

16. The method of any one of claims 10-15, wherein the compound is brivaracetam.

17. The method of any one of any one of claims 10-15, wherein the compound is levetiracetam.

18. The method of any one of claims 10-19, wherein the opioid is selected from Codeine, Fentanyl, Hydrocodone, Hydromorphone, Methadone, Oxycodone, Oxymorphone,

Buprenorphine, Methadone, Morphine, Naltrexone, Nalbuphine, Tapentadol, and Tramadol.

19. A method of any preceding claim, wherein the subject has a central nervous system injury.

20. The method of any preceding claim, wherein the pain is neuropathic pain.

21 . A method of reducing pain in a subject on an opioid therapeutic regimen comprising: administering to the subject brivaracetam or levetiracetam, and administering the opioid,

wherein the subject has a decrease in pain of at least 1 on a 0-10 pain scale as compared to administration of the opioid in the absence of brivaracetam or levetiracetam.

22. The method of claim 21 , wherein the step of administering the opioid comprises continuing the opioid therapeutic regimen of the subject.

23. The method of claim 21 , wherein the decrease in pain is at least 3 on the 0-10 pain scale.

24. The method of claim 21 , wherein the subject has been treated with an opioid for at least six months.

25. The method of claim 21 , wherein the subject has been treated with an opioid for at least twelve months.

26. The method of any one of claims 21 -25, wherein the opioid dose is maintained.