WO2007057508A2 - Treatment of pain with a combination of an alpha2 -adrenoceptor antagonist such as atipemezole or fipamezoiie and an opioid receptor agonist, such as tramadol - Google Patents

Abstract

This invention relates to use of an α2-adrenoceptor antagonist for the preparation of a medicament for treating a mammal, including human, to augment the action of a µ-opioid receptor agonist in the treatment of pain, susceptible to treatment with a µ-opioid receptor agonist, and said µ-opioid receptor agonist is a weakly efficacious µ-opioid receptor agonist or a moderately efficacious µ-opioid receptor agonist. This invention also relates to a corresponding method for the treatment or prevention of pain in a mammal, including human. This invention further relates to pharmaceutical preparations. The preparations comprise a weakly efficacious µ-opioid receptor agonist or a moderately efficacious µ-opioid receptor agonist, and a α2-adrenoceptor antagonist.

Description

TREATMENT OF PAIN

FIELD OF THE INVENTION

This invention relates to the treatment of acute and chronic pain. More specifically this invention relates to augmenting the action of a //-opioid receptor agonist in the treatment of pain.

BACKGROUND OF THE INVENTION

The publications and other materials used herein to illuminate the background of the invention, and in particular, cases to provide additional details respecting the practice, are incorporated by reference.

Noradrenergic and opioidergic systems play important roles in the modulation of pain, and the simultaneous activation of both systems is known to provide synergistic interactions at the spinal as well as supraspinal levels. The antinociceptive effects of the two transmitter systems are mediated by ^-adrenoceptors and opioid peptide receptors that both belong to the rhodopsin- like family of heptahelical cell membrane receptors. Opioid receptors and α2-adrenoceptors couple to similar pertussis toxin-sensitive Gj_/0-type G-proteins and to similar signal transduction pathways: their activation leads to inhibition of adenylyl cyclase activity, activation of K⁺ currents, inhibition of Ca²⁺ channels, and an increase in MAP kinase phosphorylation (Waldhoer et al. 2004; Richman and Regan, 1998). The involvement of opioid receptors and ^-adrenoceptors in antinociception depends on both presynaptic inhibition of neurotransmitter release and on hyperpolarization of postsynaptic neuronal membranes and their thereby reduced excitability. The plant-derived classical opioid agonist morphine and many synthetic opioid derivatives are commonly used for the treatment of severe pain, but troubling side effects such as suppression of respiration, constipation, development of tolerance requiring escalating drug doses to maintain the desired therapeutic effect and a liability to cause dependence and drug addiction limit the usefulness of this class of drugs, especially as concerns their prolonged use. In attempts to overcome these problems many approaches have been investigated, with exploitation of the synergism achievable via the simultaneous activation of opioidergic and noradrenergic receptors, i.e. the concomitant use of agonists for these two types of receptors, being one such approach.

Opioid peptide receptors are encoded by four different mammalian genes, i.e. there are four distinct opioid receptor subtypes: μ-, δ-, K- and OrphaninFQ (nociceptin) receptors (Waldhoer et al., 2004). For the prototypical analgesia compound morphine it has been shown that its analgesic efficacy, as well as most of its undesired opioidergic effects are mediated mainly by //-opioid receptors. Studies with gene-targeted (knock-out, KO) mice lacking individual opioid receptor subtypes have demonstrated that antinociception, the development of tolerance to opioid analgesia, the development of drug dependence, withdrawal symptoms, and many other classical opioid effects of morphine, such as hyperlocomotion and constipation, are absent in //-opioid receptor-deficient mice (Waldhoer et al. 2004).

For ^-adrenoceptors three different subtypes, differentiated as a2k-, CΓ₂B- and σ₂c-adrenoceptors, have been identified in humans as well as in mice. Of these subtypes, <?2A- and <7₂c-adrenoceptors show a widespread expression in the central nervous system (CNS) with the α_2A-adrenoceptor being the principal (^-adrenoceptor subtype. Presynaptically located α_2A- and ^-adrenoceptors inhibit the release of noradrenaline and several other neurotransmitters (Brede et al., 2004). The antinociceptive and sedative properties of α₂-adrenoceptor agonists are mainly attributed to α_2A-adrenoceptor activation, as evidenced by recent studies on mice lacking functional <7_2A-adrenoceptors (Lahdesmaki et al., 2002; Stone et al., 1997). It has also been reported that the activation of postsynaptic σ_2A- adrenoceptors in the prefrontal cortex is involved in working memory, behavioral inhibition and the maintenance of appropriate levels of attention (Arnsten, 2004). Postsynaptically localized tf₂c-adrenoceptors have also been found in the mouse CNS, mainly in basal ganglia, the olfactory tubercle, the hippocampus, the cerebral cortex and also in the spinal cord and brain stem (Holmberg et al., 2003). As mentioned, the brain noradrenergic system plays an important role in the modulation of opioid actions. Not only do ^-adrenoceptor agonists potentiate morphine analgesia, but in the spinal cord of mice (Ossipov et al., 1990a) and rats (Ossipov et al., 1990b) there is antinociceptive synergism between ^-noradrenergic and opioidergic pathways activated by endogenous agonists. Substance P-induced nociceptive behavioral responses in mice are inhibited by both opioid agonists and (^-adrenoceptor agonists when these agonists are administered intrathecal^ (Roerig et al., 1992). In addition, it has been shown that (^-adrenoceptors and //-opioid receptors are co-localized in proximal dendrites of primary hippocampal neurons (Jordan et al., 2003) and similar localization patterns have also been reported for the dorsal horn of the mouse spinal cord (Waldhoer et al., 2004).

In »_2A-KO mice, i.e. animals lacking αr_2A-adrenoceptors because the α_2A-adreno- ceptor gene has been silenced by targeted gene deletion, the analgesic response to α₂-adrenoceptor agonists is absent (Lahdesmaki et al., 2002; Ozdogan et al., 2004; Stone et al., 1997), as is the analgesic synergism of opioids and ^-adrenoceptor agonists. In particular the latter observation strongly confirms the central role of the ^-adrenoceptor among the three (^-adrenoceptor subtypes for the synergistic antinociceptive effect of αr₂-adrenoceptor agonists and opioid receptor agonists.

Three previous studies with morphine in α_2A-KO mice (Lahdesmaki et al., 2003) (Ozdogan et al., 2004), respectively mice with dysfunctional ^-adrenoceptors (Stone et al., 1997) have shown similar analgesic efficacy for this opioid receptor agonist when compared to wild type control animals in a tail flick analgesia model. These observations are easily compatible with the intuitive expectation that, while opioid receptor agonists and σ₂-adrenoceptor agonists can produce synergistic analgesic effects when applied concomitantly, the analgesic effects of opioid receptor agonists in the absence of a stimulatory input via ^-adrenoceptors should be comparable, independent of whether the absence of such a stimulatory σ₂- adrenoceptor input is due to the absence of an endogenous or exogenously administered <7₂-agonists, the absence of functional σ_2A-adrenoceptors or the absence of ^-adrenoceptor proteins after inactivation of the α_2A-adrenoceptor gene.

However, morphine is a highly efficacious partial //-opioid receptor agonist and is only one example of a broad range of full and partial //-opioid receptor agonists that are in clinical use for the treatment of pain.

OBJECT AND SUMMARY OF THE INVENTION

One object of the present invention is to provide means for augmenting the action of a //-opioid receptor agonist in the treatment of pain.

Another objective of the present invention is to provide a method for the treatment or prevention of pain in a mammal, including human.

A further objective of the present invention is to provide a pharmaceutical preparation for the above-mentioned means and treatment.

The present invention provides use of an σ₂-adrenoceptor antagonist for the preparation of a medicament for treating a mammal, including human, to augment the action of a //-opioid receptor agonist in the treatment of pain, susceptible to treatment with a //-opioid receptor agonist, and said //-opioid receptor agonist is a weakly efficacious //-opioid receptor agonist or a moderately efficacious //-opioid receptor agonist.

The present invention also provides a method for the treatment or prevention of pain in a mammal, including human, wherein treatment comprises administering to said mammal a //-opioid receptor agonist and an σ₂-adrenoceptor antagonist whereby the //-opioid receptor agonist is a weakly efficacious //-opioid receptor agonist or a moderately efficacious //-opioid receptor agonist, employed at a lower dose than if applied alone, and said pain is susceptible to treatment with a //-opioid receptor agonist.

The present invention further provides a pharmaceutical preparation. Characteristic for the preparation is that it comprises a weakly efficacious //-opioid receptor agonist or a moderately efficacious μ-opioid receptor agonist, and an ff₂-adrenoceptor antagonist.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1A illustrates increase in tail-flick response latency in mice after i.p. administration of saline and different doses of fentanyl after drug administration.

Figure 1 B illustrates increase in hot-plate response latency in mice after i.p. administration of saline and different doses of fentanyl after drug administration.

Figure 2A illustrates increase in tail-flick response latency in mice after i.p. administration of saline and different doses of morphine after drug administration.

Figure 2B illustrates increase in hot-plate response latency in mice after i.p. administration of saline and different doses of morphine after drug administration.

Figure 3A illustrates increase in tail-flick response latency in mice after i.p. administration of saline and different doses of buprenorphine after drug administration.

Figure 3B illustrates increase in hot-plate response latency in mice after i.p. administration of saline and different doses of buprenorphine after drug administration.

Figure 4A illustrates increase in tail-flick response latency in mice after i.p. administration of saline and different doses of tramadol after drug administration.

Figure 4B illustrates increase in hot-plate response latency in mice after i.p. administration of saline and different doses of tramadol after drug administration.

Figure 5 illustrates effects of the (^-adrenoceptor antagonist atipamezole on tramadol-induced increases in hot-plate and tail-flick response latencies in wild-type C57/BI mice. Figure 6 illustrates effects of the (^-adrenoceptor antagonist fipamezole on tramadol-induced increases in hot-plate and tail-flick response latencies in wild-type C57/BI mice.

DETAILED DESCRIPTION OF THE INVENTION

When further studying the relative antinociceptive efficacy of a number of //-opioid agonists in mice lacking the σ_2A-adrenoceptor, via the conventional and commonly employed tail-flick and hot plate tests, the Applicants have now surprisingly found that otherwise very weak opioid receptor agonists show much more pronounced analgesic effects in £/2A-KO mice compared to their wild type controls. Interestingly, this finding of much stronger analgesic effects of weak opioid receptor agonists seen in α_2A-KO mice could subsequently also be demonstrated in wild type mice when (^-adrenoceptors were blocked by the application of the α₂-adrenoceptor antagonists atipamezole or yohimbine. Both antagonists, while having no significant analgesic effects of their own, dose dependency potentiated tramadol-induced analgesia in both the tail-flick and the hot plate assay. Subsequent experiments showed that this property was also shared by another more recently discovered a₂- adrenoceptor antagonist, fipamezole.

Accordingly, the present invention relates to the treatment of acute or chronic pain in a mammal by administering to said mammal a combination of a //-opioid receptor agonist with weak or moderate intrinsic activity and an α^-adrenoceptor antagonist. It was surprisingly found that in such a combination the σ₂-adrenoceptor antagonist potentiates the analgesic effectiveness of the partial μ- opioid receptor agonist beyond the extent of pain relieve achievable by the opioid agonist alone. For example, the analgesia-potentiating effect by ^-adrenoceptor antagonists allows the weak partial //-opioid agonist tramadol to achieve the same degree of antinociceptive effectiveness as the more powerful //-opioid agonists morphine or fentanyl. Since the use of morphine and fentanyl is plagued by problems such as the development of tolerance, drug dependence, withdrawal symptoms and other side effects like hyperlocomotion and constipation, being able to achieve the same degree of pain relief with weaker partial //-opioid agonists that do not share these problems has obvious therapeutic advantages. The analgesia- potentiating effect of ^-adrenoceptor antagonists also offers the possibility to use lower doses of weakly efficacious //-opioid receptor agonists or of moderately efficacious //-opioid agonists for the same level of pain relief than when these //- opioid agonists are administered alone, permitting to deploy the weakly or moderately efficacious //-opioid agonists as sparingly as possible and thereby reduce their propensity to cause unwanted side effects.

Definitions

The term "treatment of pain" shall be understood to include the amelioration or alleviation of said condition as well as its complete curing.

The term "//-opioid agonist" shall be understood as a substance or drug that has affinity for and that activates the //-opioid receptor.

The terms "intrinsic activity" or "agonist efficacy", which are being used interchangeably, shall be understood to relate to the extent to which a compound interacting with the //-opioid receptor is capable of causing the activation of said receptor.

The term "weakly efficacious" when describing a //-opioid receptor agonist shall be understood to mean an agonist which gives rise to a maximal response that is equal to or lower than that of buprenorphine in the ³⁵S-GTPyS binding assay with membranes from SK-N-SH cells published by Selley et al (1997).

The term "moderately efficacious" when describing a //-opioid receptor agonist shall be understood to mean an agonist which gives rise to a maximal response that is equal to or lower than that of morphine but higher than that of buprenorphine in the ³⁵S-GTPyS binding assay with membranes from SK-N-SH cells published by Selley et al. (1997).

The term '^-adrenoceptor antagonist" shall be understood as a substance or drug that has affinity for and that occludes or competes with the binding of 02- adrenoceptor activating ligand such as adrenaline or noradrenaline at the a₂- adrenoceptor and therefore diminish or prevent cellular signaling which would be to due to the activation of (^-adrenoceptor by a given ligand.

The term "selective for the σ_2A-adrenoceptor" shall be understood to mean a compound having a binding affinity (expressed for example in the form of Kj values) for the (^-adrenoceptor that is at least 10 times better than those for the other a-r adrenoceptor subtypes. Such binding affinities on ^-adrenoceptor subtypes can be determined via well-established competition binding assays, for details of such assays see for example Marjamaki et al. (1992).

Preferred embodiments The invention concerns use of an (^-adrenoceptor antagonist for the preparation of a medicament for treating a mammal, including human, to augment the action of a //-opioid receptor agonist in the treatment of pain, susceptible to treatment with a //-opioid receptor agonist, and said μ-opioid receptor agonist is a weakly efficacious //-opioid receptor agonist or a moderately efficacious //-opioid receptor agonist.

The pain to be treated is typically pain selected from the group consisting of a) acute pain, where the pain is caused by i) traumatic tissue injury, ii) surgery or other medical procedure, iii) burn injury, iv) tissue hypoxia or anoxia, such as ischemic heart disease or peripheral vascular disease, and/or v) inflammation; b) chronic pain, where the pain is nociceptive pain caused by i) traumatic tissue injury, ii) surgery or other medical procedure, iii) burn injury, iv) tissue hypoxia or anoxia, such as ischemic heart disease or peripheral vascular disease, v) inflammation, vi) cancer or any other neoplastic disease process, and/or vii) non-cancerous tumor growth causing pain by expansion; c) chronic pain, where the pain is neuropathic pain caused by i) traumatic tissue injury, ii) surgery or other medical procedure, iii) burn injury, iv) tissue hypoxia or anoxia, such as ischemic heart disease or peripheral vascular disease, v) inflammation, vi) cancer or any other neoplastic disease process, vii) non-cancerous tumour growth causing pain by expansion, and/or viii) neuropathological processes involving the central or peripheral nervous system; d) break-through pain, where the pain is an acute exacerbation of chronic nociceptive or neuropathic pain; e) pain of soft tissues, joints and bones; f) deep and visceral pain; g) headaches and other head pain; h) pain caused by nerve and nerve root damage; and i) pain caused by disorders of the central nervous system.

Pain of soft tissues, joints and bones is typically pain selected from the group consisting of i) acute and postoperative pain, ii) osteoarthritis, iii) rheumatoid arthritis, iv) traumatic and inflammatory pain states of muscles, tendons and ligaments, v) chronic back pain, vi) upper extremity pain, and vii) fibromyalgia.

Deep and visceral pain is typically pain selected from the group consisting of i) abdominal pain, ii) heart, vascular and haemopathic pain, iii) chronic pelvic pain, iv) obstetric pain, and v) genitourinary pain.

Headaches and other head pain is typically selected from the group consisting of i) orofacial pain, including dental pain and pain due to temporomandibular joint disorders, ii) vascular orofacial pain, iii) burning mouth syndrome, iv) trigeminal, eye and ear pain, v) glossopharyngeal neuralgia, vi) migraine, vii) cluster headaches, viii) paroxysmal hemicrania, ix) tension headache, x) post-traumatic headache, xi) headache associated with vascular disorders or non-vascular intracranial disorders, and xii) tic douloureux.

Pain caused by nerve and nerve root damage is typically pain selected from the group consisting of i) traumatic mononeuropathies, such as entrapment neuropathies, nerve transection, causalgia, painful scars, post-thoracotomy pain and stump pain, ii) phantom pain and other pain states after amputation, iii) peripheral polyneuropathies, including diabetic, uraemic, alcoholic, drug- induced (e.g. isoniazid, cisplatin, vincristine, nitrofurantoin, disulfiram) and toxic (e.g. thallium, arsenic, clioquinol) neuropathies, iv) postherpetic neuralgia, v) complex regional pain syndromes, vi) nerve root disorders and arachnoiditis, vii) malignant nerve or plexus invasion, viii) radiation plexopathy, ix) polyneuropathies induced by metabolic and nutritional disorders, such as pellagra, amyloid deposition, beriberi, or burning feet syndrome, x) hereditary polyneuropathies, including Fabry's disease and dominantly inherited sensory neuropathy, xi) malignant polyneuropathy (e.g. myeloma, carcinomatous), and xii) acute idiopathic polyneuropathy (including Guillain-Barre syndrome).

Pain caused by disorders of the central nervous system is pain typically selected from the group consisting of i) central pain, e.g. secondary to vascular lesions, multiple sclerosis, syringomyelia, tumours, abscesses, inflammatory diseases, epilepsy or Parkinson^'s disease, and ii) pain caused by spinal cord injury or other damage of the spinal cord.

The α₂-adrenoceptor antagonist is typically selected from the group consisting of ARC 239, atipamezole, BRL 44408, CH-38083, corynanthine, deriglidole, midaglizole, efaroxan, fipamezole, fluparoxan, GPI 1485, idazoxan, imiloxan, L-659,066, mirtazapine, MK-912, Org-3770, phenoxybenzamine, piperoxan, rauwolscine, delequamine, RS-79948-197, RX-821002, SKF 104,856, SKF 86466, SL-84.0418, tolazoline, WB4101 , YNS-15P and yohimbine. The α₂-adrenoceptor antagonist is preferably selective for the (^-adrenoceptor.

If the //-opioid receptor agonist is a weakly efficacious //-opioid receptor agonist it is typically selected from the group consisting of buprenorphine, tramadol, codeine, dextropropoxyphene, nalorphine, nalbuphine and levallorphan. If the //-opioid receptor agonist is a moderately efficacious //-opioid receptor agonist it is typically selected from the group consisting of morphine, pethidine, oxycodone, methadone, pentazocine and meptazinol.

The invention also concerns the treatment or prevention of pain in a mammal, including human, wherein the treatment comprises administering to said mammal a

//-opioid receptor agonist and an ^-adrenoceptor antagonist whereby the //-opioid receptor agonist is a weakly efficacious //-opioid receptor agonist employed at a lower dose than if applied alone or a moderately efficacious //-opioid receptor agonist employed at a lower dose than if applied alone, and said pain is susceptible to treatment with a //-opioid receptor agonist.

The pain to be treated is typically selected from the pains disclosed above. The (^-adrenoceptor antagonist is typically selected from ^-adrenoceptor antagonists disclosed above. The α₂-adrenoceptor antagonist is preferably selective for the α_2A-adrenoceptor. The weakly efficacious //-opioid receptor agonist is typically selected from weakly efficacious //-opioid receptor agonist disclosed above. The moderately efficacious //-opioid receptor agonist is typically selected from the moderately efficacious //-opioid receptor agonists disclosed above.

Doses and administration routes

The analgesia-potentiating effect of ^-adrenoceptor antagonists offers the possibility to use lower doses of moderately efficacious //-opioid agonists for the same level of pain relief than when these //-opioid agonists are administered alone. The dose can possibly be reduced to one thirtieth of the dose used when these //-opioid agonists are administered alone. The use of lower doses of moderately efficacious //-opioid agonists offers the possibility to increase the amount of individual doses without increasing the total dose.

The therapeutic dose to be given to a patient or a non-human mammal in need of the treatment will vary depending on the compound being administered, the age and the sex of the subject being treated, the duration of the treatment as well as the route and method of administration, and is easily determined by the person skilled in the field. Accordingly, the typical dosage for oral administration is from 3 //g/kg to

100 mg/kg per day and for parenteral administration from 0.3 //g/kg to 10 mg/kg per day for an adult mammal. Typical dosages of different compounds are exemplified below.

As to weakly efficacious //-opioid receptor agonists, the typical dosage of buprenorphine is from 0.3 //g/kg to 0.3 mg/kg per day. The typical dosage of tramadol is from 70 //g/kg to 6 mg/kg per day. The typical dosage of codeine is from 10 //g/kg to 5 mg/kg per day. The typical dosage of dextropropoxyphene is from 90 //g/kg to 7 mg/kg per day.

As to moderately efficacious //-opioid receptor agonists, the typical dosage of morphine is from 9 //g/kg to 3 mg/kg per day. The typical dosage of oxycodone is from 8 //g/kg to 10 mg/kg per day. The typical dosage of methadone is from 7 //g/kg to 0.6 mg/kg per day.

As to ^-adrenoceptor antagonists, the typical dosage of atipamezole is from 10 //g/kg to 10 mg/kg per day. The typical dosage of fipamezole is from 10 //g/kg to 10 mg/kg per day. The typical dosage of mirtazapine is from 0.2 mg/kg to 0.7 mg/kg per day.

In some embodiments of the invention the //-opioid receptor agonist is comprised in a first medicament and the ^-adrenoceptor antagonist is comprised in a second different medicament. The formulation of the first medicament comprising the //-opioid receptor agonist is typically selected from the group consisting of i) conventional oral, ii) slow-release oral, iii) rectal suppository, iv) transdermal patch, and v) injectable depot.

The formulation of the second medicament comprising the ^-adrenoceptor antagonist is typically selected from the group consisting of i) conventional oral ii) oromucosal, and iii) injectable depot.

Preferable combination of the formulations of the first medicament comprising the //-opioid receptor agonist and the second medicament comprising the ^-adrenoceptor antagonist are respectively selected from the group consisting of i) conventional or slow-release oral, and conventional oral; ii) conventional or slow-release oral, and oromucosal tablet; iii) rectal suppository, and conventional oral; iv) rectal suppository, and oromucosal tablet; v) transdermal patch, and conventional oral; vi) transdermal patch, and oromucosal tablet; vii) injectable depot, and conventional oral; viii) injectable depot, and oromucosal tablet; and ix) injectable depot, and injectable depot.

One preferred combination of the first medicament comprising the //-opioid receptor agonist and the second medicament comprising the ^-adrenoceptor antagonist is respectively a combination of a transdermal patch and an oromucosal tablet wherein preferably the //-opioid receptor agonist is buprenorphine and the ^-adrenoceptor antagonist is fipamezole or atipamezole. In other embodiments of the invention the //-opioid receptor agonist and the ^-adrenoceptor antagonist are comprised in the same medicament. The formulation of the medicament is typically selected from the group consisting of i) conventional tablet, ii) conventional capsule, iii) slow-release tablet or capsule, iv) oromucosal tablet, v) rectal suppository, vi) transdermal patch, vii) conventional injectable, and viii) injectable depot.

Preferably the formulation of the medicament is an injectable depot to be injected at intervals of at least one week, preferably two weeks or longer.

The invention also concerns pharmaceutical preparations. Characteristic for a typical preparation according to the invention is that it comprises a weakly efficacious //-opioid receptor agonist or a moderately efficacious //-opioid receptor agonist, and an α₂-adrenoceptor antagonist. The ^-adrenoceptor antagonist is typically selected from α₂-adrenoceptor antagonists disclosed above. The ^-adrenoceptor antagonist is preferably selective for the α_2A-adrenoceptor. The weakly efficacious //-opioid receptor agonist is typically selected from weakly efficacious //-opioid receptor agonist disclosed above. The moderately efficacious //-opioid receptor agonist is typically selected from the moderately efficacious //-opioid receptor agonists disclosed above.

The formulation of the pharmaceutical preparation according to the invention is selected from the group consisting of i) conventional tablet, ii) conventional capsule, iii) slow-release tablet or capsule, iv) oromucosal tablet, v) rectal suppository, vi) transdermal patch, vii) conventional injectable, and viii) injectable depot.

Preferably the formulation of the pharmaceutical preparation is an injectable depot.

One preferred embodiment of the preparation is a controlled release sterile injectable formulation, which upon injection releases the ^-adrenoceptor antagonist and the //-opioid receptor agonist over a period of at least one week. The embodiment comprises the (^-adrenoceptor antagonist and the //-opioid receptor agonist, and their vehicle, comprising one or more suspending agents, (e.g. carboxymethylcellulose), the bulking agent (e.g. mannitol) and a buffer (e.g. sodium phosphate), in water for injection. The formulation can be administered intramuscularly or subcutaneously.

Another preferred embodiment of the preparation is a depot release sterile injectable formulation, which upon injection releases the ^-adrenoceptor antagonist and the //-opioid receptor agonist over a period of at least one week. This embodiment can comprise the compounds being microencapsulated in, or attached to, a slow release or targeted delivery systems, such as biocompatible, biodegradable polymer matrices, e.g. poly(d,1-lactide co-glycolide), liposomes and microspheres. Such embodiments can be subcutaneously or intramuscularly injected by a technique called subcutaneous or intramuscular depot to provide continuous slow release of the α₂-adrenoceptor antagonist and the //-opioid receptor agonist.

Description of the drawings

Fig. 1A illustrates increase in tail-flick response latency after i.p. administration of saline and four different doses of fentanyl (0.02, 0.05, 0.1 and 0.5 mg/kg) at three time points (10, 30 and 60 min) after drug administration. The experiments were carried out in two groups of mice, C57/BI control (wild-type, WT) and ^-adrenoceptor knock-out (KO) mice. Tail-flick latencies were converted to percentage of Maximal Possible Effect (% MPE). Means ± S. E. M.; no statistically significant differences were observed between the mouse genotypes.

Fig. 1 B illustrates increase in hot-plate response latency after i.p. administration of saline and four different doses of fentanyl (0.02, 0.05, 0.1 and 0.5 mg/kg) at three time points (10, 30 and 60 min) after drug administration. The experiments were carried out in two groups of mice, C57/BI control (wild-type, WT) and <72A- adrenoceptor knock-out (KO) mice. Hot-plate latencies were converted to percentage of Maximal Possible Effect (% MPE). No statistically significant differences were observed between the mouse genotypes.

Fig. 2A illustrates increase in taii-flick response latency after i.p. administration of saline and three different doses of morphine (2, 5 and 10 mg/kg) at 30 min after drug administration. The experiments were carried out in two groups of mice, C57/BI control (wild-type, WT) and (^-adrenoceptor knock-out (KO) mice. Tail-flick latencies were converted to percentage of Maximal Possible Effect (% MPE). *** denotes statistically significant genotype difference (two-way ANOVA followed by t- test; P<0.001 ).

Fig. 2B illustrates increase in hot-plate response latency after i.p. administration of saline and three different doses of morphine (2, 5 and 10 mg/kg) at 30 min after drug administration. The experiments were carried out in two groups of mice, C57/BI control (wild-type, WT) and (^-adrenoceptor knock-out (KO) mice. Hotplate latencies were converted to percentage of Maximal Possible Effect (% MPE). No statistically significant differences were observed between the mouse genotypes.

Fig. 3A illustrates increase in tail-flick response latency after i.p. administration of saline and four different doses of buprenorphine (0.5, 1 , 2 and 3 mg/kg) at two time points (60 and 120 min) after drug administration. The experiments were carried out in two groups of mice, C57/BI control (wild-type, WT) and σ_2A-adrenoceptor knockout (KO) mice. Tail-flick latencies were converted to percentage of Maximal Possible Effect (% MPE). Asterisks denote significant differences between the genotypes (two-way ANOVA followed by t-tests; * P<0.05, ** PO.01 , *** P<0.001 ).

Fig. 3B illustrates increase in hot-plate response latency after i.p. administration of saline and four different doses of buprenorphine (0.5, 1 , 2 and 3 mg/kg) at two time points (60 and 120 min) after drug administration. The experiments were carried out in two groups of mice, C57/BI control (wild-type, WT) and α_2A-adrenoceptor knockout (KO) mice. Hot-plate latencies were converted to percentage of Maximal Possible Effect (% MPE). Asterisks denote significant differences between the genotypes (two-way ANOVA followed by t-tests; * P<0.05, ** PO.01 , *** P<0.001).

Fig. 4A illustrates increase in tail-flick response latency after i.p. administration of saline and five different doses of tramadol (2.5, 5, 10, 20 and 40 mg/kg) at 30 min after drug administration. The experiments were carried out in two groups of mice, C57/BI control (wild-type, WT) and α_2A-adrenoceptor knock-out (KO) mice. Tail-flick latencies were converted to percentage of Maximal Possible Effect (% MPE). Asterisks denote significant differences between the genotypes (two-way ANOVA followed by t-tests; * P<0.05, ** PO.01 , *** PO.001).

Fig. 4B illustrates increase in hot-plate response latency after i.p. administration of saline and five different doses of tramadol (2.5, 5, 10, 20 and 40 mg/kg) at 30 min after drug administration. The experiments were carried out in two groups of mice, C57/BI control (wild-type, WT) and (^-adrenoceptor knock-out (KO) mice. Hotplate latencies were converted to percentage of Maximal Possible Effect (% MPE). Asterisks denote significant differences between the genotypes (two-way ANOVA followed by t-tests; * P<0.05, ** PO.01 , *^** PO.001 ).

Fig. 5 illustrates effects of the ^-adrenoceptor antagonist atipamezole (0.1 , 0.5, 1 and 3 mg/kg) on tramadol-induced increases in hot-plate and tail-flick response latencies in wild-type C57/BI mice. Saline or atipamezole were administered s.c. 5 min before tramadol (40 mg/kg). Responses were measured 30 min after tramadol administration. *** denotes significant differences compared to the saline-pretreated group (Scheffe-tests; PO.001). Fig. 6. illustrates effects of the ^-adrenoceptor antagonist fipamezole (0.3, 1 and 3 mg/kg) on tramadol-induced increases in hot-plate and tail-flick response latencies in wild-type C57/BI mice. Saline or fipamezole were administered s.c. 5 min before tramadol (40 mg/kg). Responses were measured 30 min after tramadol administration. Asterisks denote significant differences compared to the saline- pretreated group (Scheffe-tests; *** PO.001 , ** P<0.01 ).

It will be appreciated that the subject matter of the present invention can be incorporated in the form of a variety of embodiments, only a few of which are disclosed herein. It will be apparent for the person skilled in the field that other embodiments exist and do not depart from the scope of the invention. Thus, the described embodiments are illustrative and should not be construed as restrictive

EXPERIMENTAL SECTION

Animals

Male C57BI/6J control mice and mice with targeted disruption of the α_2A-adrenoceptor gene (<7₂A-KO) weighing 20-35 g were used. The generation of an α_2A-KO mouse line has been described previously (Altman et al., 1999). The σ_2A-KO mice were backcrossed to C57BI/6J mice for a minimum of five generations to produce a congenic line. Animals were allowed free access to food (RM 3 standard pellets, SDS, U.K.) and tap water, and were kept under artificial light for 12 h each day in a room with controlled temperature (21 ⁰C) and humidity (50±10 %). All experiments were approved by the local committee for animal welfare and were in accordance with the European Communities Council Directive of 24 November 1986 (86/906/EEC). The same groups of mice were subjected to the entire test protocol. The number n of animal per group was 9 or 10.

Drugs

Morphine HCI and yohimbine HCI (Sigma, St. Louis, MO), tramadol HCI (Tramadol Generics^®, Therabel Pharma, Rotterdam, The Netherlands), fentanyl HCI (Fentanyl^®, Janssen-Cilag, Beerse, Belgium), buprenorphine (Temgesic^®, Schering- Plough, Brussels, Belgium), atipamezole (Orion Pharma, Turku, Finland) and fipamezole (Juvantia Pharma, Turku, Finland) were obtained from the indicated sources. The drugs were dissolved in or diluted into physiological saline, which was also used as the control vehicle. All drugs were administered in a volume of 10 ml/kg i.p. or s.c. ((^-adrenoceptor antagonists).

Antinociceptive tests Drug-induced antinociception was assessed with the tail-flick method with a cut-off time of 10 s using a commercial tail-flick analgesiameter (Ugo Basile, Comercio, Italy) and with the hot-plate method at a temperature of 55 ⁰C and a cut-off time of 15 s using a commercial hot-plate analgesiameter (ITC Inc., Woodlands Hills, CA). In the hot-plate test, the mice were placed on a metal plate surrounded by a clear plastic chamber. The latency to lick one of the hind paws or to jump off the plate was measured. Basal tail-flick and hot-plate scores were first measured, followed by a second tail-flick and hot-plate measurement after i.p. administration of the test drugs or saline alone. The assessments were repeated after suitable intervals, depending on the duration of action of the investigated agents (see Figures for time points). Tail-flick and hot-plate latencies were converted into percent of Maximal Possible Effect (% MPE) according to the following formula: % MPE = (measured latency - basal latency) / (cut-off time - basal latency) x 100 %.

Statistical analysis The analgesic effects of each drug were tested employing a two-way analysis of variance (ANOVA) followed by Scheffe post hoc tests using the SPSS program package (SPSS 8.0 for Windows, SPSS Inc., Chicago, IL). Different drug treatments and antagonists were compared to saline-treated groups using independent samples t-tests. Non-parametric data were compared using the Mann- Whitney U-test. Results are presented as mean ± S.E.M. The level of significance was set at P<0.05. Example 1

Effects of the μ-opioid agonist fentanyl on tail-flick and hot-plate latency in wild-type

Using the assay protocols described under 'Antinociceptive tests' the results depicted in Fig. 1A for the tail-flick latency assay and in Fig. 1 B for the hot-plate latency assay were obtained with the μ-opioid receptor agonist fentanyl. As can be seen from these two figures, the fentanyl-induced analgesic responses were similar in wild-type and CT₂A-KO animals and no significant differences between the two genotypes were observed.

Example 2

Effects of the μ-opioid agonist morphine on tail-flick and hot-plate latency in wild-

Using the assay protocols described under 'Antinociceptive tests' the results depicted in Fig. 2A for the tail-flick latency assay and in Fig. 2B for the hot-plate latency assay were obtained with the //-opioid receptor agonist morphine. As can be seen from Fig. 2B, no significant differences between the wild-type and the CT₂A-KO animals were detected in terms of hot-plate latency. For the tail-flick latency shown in Fig. 2A the antinociceptive effect of morphine was somewhat more accentuated in the CT₂A-KO mice compared to the wild-type animals, a difference that reached statistically significant levels for the highest dose of 10 mg/kg morphine (P<0.01 in two-way ANOVA).

Example 3

Effects of the μ-opioid agonist buprenorphine on tail-flick and hot-plate latency in wild-type and CT_∑A-KO mice Using the assay protocols described under 'Antinociceptive tests' the results depicted in Fig. 3A for the tail-flick latency assay and in Fig. 3B for the hot-plate latency assay were obtained with the μ-opioid receptor agonist buprenorphine. As can be seen from these two figures, the analgesic responses to buprenorphine were for the majority of doses and time points clearly more accentuated in the case of the CT₂A-KO mice than the wild-type animals. In the tail-flick latency assay (Fig. 3A) the genotype differences reached statistically significant levels for most of the buprenorphine doses, independent of whether the buprenorphine effects were determined 60 minutes or 120 minutes after the application of the drug.

Example 4 Effects of the μ-opioid agonist tramadol on tail-flick and hot-plate latency in wild- type and ct_2A-KO mice

Using the assay protocols described under 'Antinococeptive tests' the results depicted in Fig. 4A for the tail-flick latency assay and in Fig. 4B for the hot-plate latency assay were obtained with the μ-opioid receptor agonist tramadol. As can be seen from Fig. 4A and 4B, the analgesic responses to tramadol were very markedly accentuated in the ^_2A-KO mice in both antinociceptive tests (genotype x drug interaction: P<0.001 in two-way ANOVA in both tests).

Example 5

Potentiation of the analgesic effects of tramadol on tail-flick and hot-plate latency in wild-type mice by the α_∑-adrenocpetor antagonists atipamezole and fipamezole

Using the assay protocols described under 'Antinociceptive tests' two different ^-adrenoceptor antagonists, atipamezole and fipamezole, were tested as pretreatment before a 40 mg/kg tramadol administration in wild-type mice. Neither of the two (^-antagonists displayed any significant analgesic effects when given alone (not shown), but both, atipamezole (Fig. 5) as well as fipamezole (Fig. 6), potentiated the tramadol-induced analgesia in a dose-dependent and statistically significant manner in the two analgesic tests.

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Claims

1. Use of an σ₂-adrenoceptor antagonist for the preparation of a medicament for treating a mammal, including human, to augment the action of a //-opioid receptor agonist in the treatment of pain, susceptible to treatment with a //-opioid receptor agonist, and said //-opioid receptor agonist is a weakly efficacious //-opioid receptor agonist or a moderately efficacious //-opioid receptor agonist.

2. The use according to claim 1 characterized in that the pain is selected from the group consisting of a) acute pain, where the pain is caused by i) traumatic tissue injury, ii) surgery or other medical procedure, iii) bum injury, iv) tissue hypoxia or anoxia, and/or v) inflammation; b) chronic pain, where the pain is nociceptive pain caused by i) traumatic tissue injury, ii) surgery or other medical procedure, iii) burn injury, iv) tissue hypoxia or anoxia, v) inflammation, vi) cancer or any other neoplastic disease process, and/or vii) non-cancerous tumor growth causing pain by expansion; c) chronic pain, where the pain is neuropathic pain caused by i) traumatic tissue injury, ii) surgery or other medical procedure, iii) burn injury, iv) tissue hypoxia or anoxia, v) inflammation, vi) cancer or any other neoplastic disease process, vii) non-cancerous tumour growth causing pain by expansion, and/or viii) neuropathological processes involving the central or peripheral nervous system; d) break-through pain, where the pain is an acute exacerbation of chronic nociceptive or neuropathic pain; e) pain of soft tissues, joints and bones; f) deep and visceral pain; g) headaches and other head pain; h) pain caused by nerve and nerve root damage; and i) pain caused by disorders of the central nervous system.

3. The use according to claim 2 characterized in that the pain is pain of soft tissues, joints and bones selected from the group consisting of i) acute and postoperative pain, ii) osteoarthritis, iii) rheumatoid arthritis, iv) traumatic and inflammatory pain states of muscles, tendons and ligaments, v) chronic back pain, vi) upper extremity pain, and vii) fibromyalgia.

4. The use according to claim 2 characterized in that the pain is deep and visceral pain selected from the group consisting of i) abdominal pain, ii) heart, vascular and haemopathic pain, iii) chronic pelvic pain, iv) obstetric pain, and v) genitourinary pain.

5. The use according to claim 2 characterized in that the pain is headaches and other head pain selected from the group consisting of i) orofacial pain, ii) vascular orofacial pain, iii) burning mouth syndrome, iv) trigeminal, eye and ear pain, v) glossopharyngeal neuralgia, vi) migraine, vii) cluster headaches, viii) paroxysmal hemicrania, ix) tension headache, x) post-traumatic headache, xi) headache associated with vascular disorders or non-vascular intracranial disorders, and xii) tic douloureux.

6. The use according to claim 2 characterized in that the pain is pain caused by nerve and nerve root damage selected from the group consisting of i) traumatic mononeuropathies, ii) phantom pain and other pain states after amputation, iii) peripheral polyneuropathies, iv) postherpetic neuralgia, v) complex regional pain syndromes, vi) nerve root disorders and arachnoiditis, vii) malignant nerve or plexus invasion, viii) radiation plexopathy, ix) polyneuropathies induced by metabolic and nutritional disorders, x) hereditary polyneuropathies, xi) malignant polyneuropathy, and xii) acute idiopathic polyneuropathy.

7. The use according to claim 2 characterized in that the pain is pain caused by disorders of the central nervous system selected from the group consisting of i) central pain, and ii) pain caused by spinal cord injury or other damage of the spinal cord.

8. The use according to any of preceding claims 1 to 7 characterized in that the ^-adrenoceptor antagonist is selected from the group consisting of ARC 239, atipamezole, BRL 44408, CH-38083, corynanthine, deriglidole, midaglizole, efaroxan, fipamezole, fluparoxan, GPI 1485, idazoxan, imiloxan, L-659,066, mirtazapine, MK-912, Org-3770, phenoxybenzamine, piperoxan, rauwolscine, delequamine, RS-79948-197, RX-821002, SKF 104,856, SKF 86466, SL-84.0418, tolazoline, WB4101 , YNS-15P and yohimbine.

9. The use according to any of preceding claims 1 to 7 characterized in that the ^-adrenoceptor antagonist is selective for the α₂A-adrenoceptor.

10. The use according to any of the preceding claims 1 to 9 characterized in that the //-opioid receptor agonist is a weakly efficacious //-opioid receptor agonist selected from the group consisting of buprenorphine, tramadol, codeine, dextropropoxyphene, nalorphine, nalbuphine and levallorphan.

11. The use according to any of the preceding claims 1 to 9 characterized in that the //-opioid receptor agonist is a moderately efficacious //-opioid receptor agonist selected from the group consisting of morphine, pethidine, oxycodone, methadone, pentazocine and meptazinol.

12. A method for the treatment or prevention of pain in a mammal, including human, wherein the treatment comprises administering to said mammal a //-opioid receptor agonist and an ^-adrenoceptor antagonist whereby the //-opioid receptor agonist is a weakly efficacious //-opioid receptor agonist employed at a lower dose than if applied alone or a moderately efficacious //-opioid receptor agonist employed at a lower dose than if applied alone, and said pain is susceptible to treatment with a //-opioid receptor agonist.

13. The method according to claim 12 wherein the pain is selected from the group consisting of a) acute pain, where the pain is caused by i) traumatic tissue injury, ii) surgery or other medical procedure, iii) burn injury, iv) tissue hypoxia or anoxia, and/or v) inflammation; b) chronic pain, where the pain is nociceptive pain caused by i) traumatic tissue injury, ii) surgery or other medical procedure, iii) burn injury, iv) tissue hypoxia or anoxia, v) inflammation, vi) cancer or any other neoplastic disease process, and/or vii) non-cancerous tumour growth causing pain by expansion; c) chronic pain, where the pain is neuropathic pain caused by i) traumatic tissue injury, ii) surgery or other medical procedure, iii) burn injury, iv) tissue hypoxia or anoxia, v) inflammation, vi) cancer or any other neoplastic disease process, vii) non-cancerous tumor growth causing pain by expansion, and/or viii) neuropathological processes involving the central or peripheral nervous system; d) break-through pain, where the pain is an acute exacerbation of chronic nociceptive or neuropathic pain; e) pain of soft tissues, joints and bones; f) deep and visceral pain; g) headaches and other head pain; h) pain caused by nerve and nerve root damage; and i) pain caused by disorders of the central nervous system.

14. The method according to claim 13 wherein the pain is pain of soft tissues, joints and bones selected from the group consisting of i) acute and postoperative pain, ii) osteoarthritis, iii) rheumatoid arthritis, iv) traumatic and inflammatory pain states of muscles, tendons and ligaments, v) chronic back pain, vi) upper extremity pain, and vii) fibromyalgia.

15. The method according to claim 13 wherein the pain is deep and visceral pain selected from the group consisting of i) abdominal pain, ii) heart, vascular and haemopathic pain, iii) chronic pelvic pain, iv) obstetric pain, and v) genitourinary pain.

16. The use according to claim 13 wherein the pain is headaches and other head pain selected from the group consisting of i) orofacial pain, ii) vascular orofacial pain, iii) burning mouth syndrome, iv) trigeminal, eye and ear pain, v) glossopharyngeal neuralgia, vi) migraine, vii) cluster headaches, viii) paroxysmal hemicrania, ix) tension headache, x) post-traumatic headache, xi) headache associated with vascular disorders or non-vascular intracranial disorders, and xii) tic douloureux.

17. The method according to claim 13 wherein the pain is pain caused by nerve and nerve root damage selected from the group consisting of i) traumatic mononeuropathies, ii) phantom pain and other pain states after amputation, iii) peripheral polyneuropathies, iv) postherpetic neuralgia, v) complex regional pain syndromes, vi) nerve root disorders and arachnoiditis, vii) malignant nerve or plexus invasion, viii) radiation plexopathy, ix) polyneuropathies induced by metabolic and nutritional disorders, x) hereditary polyneuropathies, xi) malignant polyneuropathy, and xii) acute idiopathic polyneuropathy.

18. The method according to claim 13 wherein the pain is pain caused by disorders of the central nervous system selected from the group consisting of i) central pain, and ii) pain caused by spinal cord injury or other damage of the spinal cord.

19. The method according to claim 12 wherein the ^-adrenoceptor antagonist is selected from the group consisting of ARC 239, atipamezole, BRL 44408, CH-

38083, corynanthine, deriglidole, midaglizole, efaroxan, fipamezole, fluparoxan, GPI 1485, idazoxan, imiloxan, L-659,066, mirtazapine, MK-912, Org-3770, phenoxybenzamine, piperoxan, rauwolscine, delequamine, RS-79948-197, RX- 821002, SKF 104,856, SKF 86466, SL-84.0418, tolazoline, WB4101 , YNS-15P and yohimbine.

20. The method according to claim 12 wherein the α₂-adrenoceptor antagonist is selective for the σ_2A-adrenoceptor.

21. The method according to claim 12 wherein the //-opioid receptor agonist is a weakly efficacious //-opioid receptor agonist selected from the group consisting of buprenorphine, tramadol, codeine, dextropropoxyphene, nalorphine, nalbuphine and levallorphan.

22. The method according claim 12 wherein the //-opioid receptor agonist is a moderately efficacious //-opioid receptor agonist selected from the group consisting of morphine, pethidine, oxycodone, methadone, pentazocine and meptazinol.

23. The use according to any of claims 1 to 11 or the method according to any of claims 12 to 22 characterized in that the //-opioid receptor agonist is comprised in a first medicament and the ^-adrenoceptor antagonist is comprised in a second different medicament.

24. The use or method according to claim 23 characterized in that the formulation of the first medicament comprising the μ-opioid receptor agonist is selected from the group consisting of i) conventional oral, ii) slow-release oral, iii) rectal suppository, iv) transdermal patch, and v) injectable depot.

25. The use or method according to claims 23 or 24 characterized in that the formulation of the second medicament comprising the σ₂-adrenoceptor antagonist is selected from the group consisting of i) conventional oral ii) oromucosal, and iii) injectable depot.

26. The use or method according to claims 24 and 25 characterized in that the combination of the formulations of the first medicament comprising the μ-opioid receptor agonist and the second medicament comprising the ^-adrenoceptor antagonist are respectively selected from the group consisting of i) conventional or slow-release oral, and conventional oral; ii) conventional or slow-release oral, and oromucosal tablet; iii) rectal suppository, and conventional oral; iv) rectal suppository, and oromucosal tablet; v) transdermal patch, and conventional oral; vi) transdermal patch, and oromucosal tablet; vii) injectable depot, and conventional oral; viii) injectable depot, and oromucosal tablet; and ix) injectable depot, and injectable depot.

27. The use or method according to claim 26 characterized in that the combination of the first medicament comprising the //-opioid receptor agonist and the second medicament comprising the ^-adrenoceptor antagonist is respectively a combination of a transdermal patch and an oromucosal tablet wherein the //-opioid receptor agonist is buprenorphine and the ^-adrenoceptor antagonist is fipamezole or atipamezole.

28. The use according to any of claims 1 to 11 or the method according to any of claims 12 to 22 characterized in that the //-opioid receptor agonist and the

<7₂-adrenoceptor antagonist are comprised in the same medicament.

29. The use or method according to claim 28 characterized in that the formulation of the medicament is selected from the group consisting of i) conventional tablet, ii) conventional capsule, iii) slow-release tablet or capsule, iv) oromucosal tablet, v) rectal suppository, vi) transdermal patch, vii) conventional injectable, and viii) injectable depot.

30. The use or method according to claim 29 characterized in that the formulation of the medicament is an injectable depot to be injected at intervals of at least one week, preferably two weeks or longer.

31. A pharmaceutical preparation characterized in that it comprises a weakly efficacious //-opioid receptor agonist or a moderately efficacious //-opioid receptor agonist, and an α₂-adrenoceptor antagonist.

32. The pharmaceutical preparation according to claim 31 characterized in that the ^-adrenoceptor antagonist is selected from the group consisting of ARC 239, atipamezole, BRL 44408, CH-38083, corynanthine, deriglidole, midaglizole, efaroxan, fipamezole, fluparoxan, GPI 1485, idazoxan, imiloxan, L-659,066, mirtazapine, MK-912, Org-3770, phenoxybenzamine, piperoxan, rauwolscine, delequamine, RS-79948-197, RX-821002, SKF 104,856, SKF 86466, SL-84.0418, tolazoline, WB4101 , YNS-15P and yohimbine.

33. The pharmaceutical preparation according to claims 31 or 32 characterized in that the α₂-adrenoceptor antagonist is selective for the (^-adrenoceptor.

34. The pharmaceutical preparation according to claims 31 , 32 or 33 characterized in that the //-opioid receptor agonist is a weakly efficacious //-opioid receptor agonist selected from the group consisting of buprenorphine, tramadol, codeine, dextropropoxyphene, nalorphine, nalbuphine and levallorphan.

35. The pharmaceutical preparation according to any of claims 31 , 32 or 33 characterized in that the //-opioid receptor agonist is a moderately efficacious //-opioid receptor agonist selected from the group consisting of morphine, pethidine, oxycodone, methadone, pentazocine and meptazinol.

36. The pharmaceutical preparation according to any of claims 31 to 35 characterized in that the formulation of the pharmaceutical preparation is selected from the group consisting of i) conventional tablet, ii) conventional capsule, iii) slow-release tablet or capsule, iv) oromucosal tablet, v) rectal suppository, vi) transdermal patch, vii) conventional injectable, and viii) injectable depot.

37. The pharmaceutical preparation according to claim 36 characterized in that the formulation of the pharmaceutical preparation is an injectable depot.