WO2010128873A1

WO2010128873A1 - Combination of an opioid analgesic and an n-type calcium channel blocker for treating chronic pain

Info

Publication number: WO2010128873A1
Application number: PCT/PL2010/050016
Authority: WO
Inventors: Andrzej Lipkowski; Jerzy Jarosz
Original assignee: Instytut Medycyny Doświadczalnej I Klinicznej Im. Mirosława Mossakowskiego Polskiej Akademii Nauk
Priority date: 2009-05-07
Filing date: 2010-05-07
Publication date: 2010-11-11
Also published as: PL387984A1

Abstract

We disclose the use of mixtures of opioid analgesics with compounds that block type N calcium channels of the nervous system. Due to the synergistic interaction between the opioid with the compounds blocking the calcium channels, one achieves an increased analgesic activity facilitating longer effective use due to a depressed induction of tolerance to the drug. The mixtures are useful in the treatment of chronic pain caused by rheumatism, gout, neurodegeneration, postoperative or post accidental trauma, or by cancer.

Description

COMBINATION OF AN OPIOID ANALGESIC AND AN N-TYPE CALCIUM CHANNEL BLOCKER FOR TREATING CHRONIC PAIN

The subject of the present invention comprises novel compositions of medicinal substances for the treatment of chronic pain whose chief components are opioid analgesics as well as blockers of nerve cell calcium channels. The medicinal substance compositions constitute components of tablets for oral administration or they may be components of substances for transdermal administration or subdermal implants or drips or injections used in the treatment of strong, chronic pain during rheumatoid inflammation, gout or neuropathic pain connected with osteoporosis or posttraumatic or post-operational complications or tumors.

A pain signal arising as a result of tissue damage or disease is transferred to the central nervous system where it generates the sensation of pain. The magnitude of the pain signal is regulated by a system of nociceptive and anti-nociceptive receptors scattered throughout the membrane. Stimulatory tachykinin and amino acid receptors found on the neurons of the central and peripheral nervous systems constitute a significant component of the nociceptive receptor system and play a main role in the transfer of pain signals. Calcium channels play an important role in the stimulation of the nociceptive system. The transfer of a pain signals requires a change in the permeability of the cell membrane to calcium ions. Endogenous opioid peptides are one of the natural factors which dampen a pain signal caused by the activation of the nociceptive receptors through the activation of anti-nociceptive receptors. Opioid receptors are also activated through the administration of opioid analgesics such as morphine or phentanyl. Unfortunately, the administration of analgesic drugs available today causes a number of undesirable reactions, including tolerance and dependencies. Both the tolerance to the administered drug and dependencies arise as a result of the plastic adaptation of the nervous system to the administered opioids. It seems that the adaptive processes include changes in the permeability of the cell membrane to calcium ions. As described in the report by the team lead by Peter S. Staats, entitled "Intrathecal Ziconotide in the Treatment of Refractory Pain in Patients With Cancer or AIDS. A Randomized Controlled Trial." JAMA, vol. 291, 2004 pp. 63-70, the use of the peptide ziconotide, an analog of conotoxin (a strong blocker of type N calcium channels in nerve cells) exerted a very strong analgesic effect against chronic pain, including that caused by cancer. However, the compound must be administered subarachnoidally because it does not pass through the brain-blood barrier and causes a number of toxic effects following peripheral administration. A number of type N calcium channel blockers have been used clinically, including cinnarizine and flunnarizine. These compounds are well tolerated by patients and have been admitted for use in humans. However, their capability of blocking calcium channels in the nervous system is low enough that they have not been found useful as analgesics for chronic pain, but are effective in treating migraines.

Unexpectedly, it turns out that the administration of weak type N calcium channel blockers such as flunnarizine or cinnarizine greatly enhances the analgesic effect of opioid analgesics. Equally unexpectedly, it turns out that the simultaneous administration of calcium channel blockers with opioid analgesics greatly delays the drug tolerance of opioids. For this reason, the combined administration of calcium channel blockers with opioids constitutes a novel, more effective solution in the treatment of pain, particularly of chronic pain such as cancer, neuropathic, rheumatoid, gout, and phantom pain or the like. The subject of the present invention are mixtures of calcium channel blockers with opioid analgesics for use in the treatment of chronic pain caused by disease or postoperative states or due to trauma.

According to the present invention, the opioid analgesic used can be any known compound which interacts with an opioid receptor. In particular this can be an opioid analgesic such as morphine or phentanyl or a derivative or analogue thereof. It is also possible to use opioid peptides and their derivatives Or analogues, in particular biphaline or its analogues.

To better illustrate the subject invention, based on the analgesic activity of mixtures of calcium channel blockers and opioid analgesics, the attached examples demonstrate the activity of the compounds in animal pain models. The scope of the present invention, however, should not be limited solely to the following examples. Example 1. A mixture was prepared of morphine hydrochloride and flunnarizine hydrochloride at a ratio of 1:5 by mass. This mixture was injected into mice intraperitoneally at a rate of 12 mg/kg. At the same time, a control group was examined which was given only morphine hydrochloride at a corresponding dose of 2 mg/kg. In both groups, the anti-nociceptive effect was examined using the tail withdrawal delay test from water at a temperature of 55°C. It turned out that the combination of flunnarizine and morphine increases the analgesic effect more than twofold. Example 2.

We examined the degree of induction of tolerance to opioid analgesics in mice. The control group was given a twice-daily, intraperitoneal dose of 2 mg/kg of morphine hydrochloride.

After five days, the animals were left for one day without drugs. On the seventh day we examined the analgesic effect of 2 mg of morphine hydrochloride administered intraperitoneally. It turned out that no analgesic effect was observed as a result of the built-up tolerance. The identical protocol was used to administer a 12 mg of a mixture of 2 mg of morphine hypochloride and 10 mg of flunnarizine hydrochloride. During the evaluation of the reaction to pain using the tail withdrawal test, we obtained a significant anti-nociceptive effect which comprised 75% of the effect induced by the same dose in animals without the prior administration of analgesics [as described in example I]. The dose given was 12 mg of the mixture, administered on the seventh day. Example 3

Inflammation was induced in mice through the administration of Freund's adjuvant into the murine limb. A progressive inflammation was observed after two days. The induced inflammation entailed the induction of nociceptive hypersensitivity in the limb. A gentle touch [von Frey test] caused the immediate withdrawal of the limb. The intraperitoneal administration of 2 mg of morphine hydrochloride to the animal decreased the hypersensitivity. The effectiveness of the administered morphine hydrochloride was weaker on the second day. On the third day, the administration of the same dose of morphine induced no decrease in hypersensitivity. At the same time we examined other animals according to the same protocol, who had been given 2 mg of morphine hydrochloride with 8 mg of cinnarizine hydrochloride. Throughout the three days of evaluation, we observed a strong hypersensitivity dampening effect. The effectiveness of the administered mixture of compounds did not change throughout the three days of the experimental duration.

Claims

1. The use of a composition comprising an opioid analgesic and a compound which blocks type N calcium channels of the nervous system in the production of a drug for the treatment of strong, chronic pain.

2. A use according to claim 1, characterized in that the drug produced is meant for oral, transdermal, or anal peripheral administration or local administration into selected structures of the central nervous system.

3. A use according to claim 1, characterized in that the drug produced is meant for the treatment of strong, chronic pain occurring during rheumatoid states, neuropathy or cancer.

4. A use according to claim 1, characterized in that the drug produced is in the form of a solution for injection or implants, pills for oral administration, suppositories for anal administration, or liquids for intravenous, subarachnoid, or epidural administration or in the form of implants or preparations for transdermal administration.

5. A composition with analgesic activity, particularly for the treatment of strong, chronic pain, characterized in that it contains an opioid analgesic and a compound that blocks type N calcium channels of the nervous system, contained in a mass ratio between 1:1 to 1:30.