[Sertürner and morphine--a historical vignette]. / Sertürner und Morphin--eine historische Vignette.

Friedrich Wilhelm Sertürner was born near Paderborn in 1783. At the age of twenty he passed examinations as a pharmacist's assistant in Paderborn. In a letter to the editor of Trommsdorffs Journal der Pharmacie Vol 13 (1805) he reported on the isolation of a substance from opium which showed alkaline character and was later called by him "morphine". In 1806, Sertürner moved to Einbeck where he first worked as assistant to the tenant of the magistrate's pharmacy. In 1809, he became pharmacist and, since the tenant was already 75 years old, he intended to take charge of the pharmacy. However,he was not successful. During the invasion of Napoleon Bonaparte's troops into Europe, French legislation became valid in those parts which fell under French government. According to French law, Sertürner was allowed to open a second pharmacy. In Einbeck, Sertürner continued research work on morphine and published the results in two papers. In one of these (1817), he introduced observations made with the drug in humans and for the first time called it "morphine". The French chemist Gay-Lussac showed interest in that publication and ordered a translation into French which earned Sertürner the scientific break-through. His was the first achievement in alkaloid research, and for that he received a doctor degree from the university of Jena in 1817.When Napoleon was finally defeated, Sertürner had to close his pharmacy in Einbeck and found another one in Hameln. When asiatic cholera spread in Germany in 1831, he postulated that cholera is caused by a poisonous,animated reproducing organism and made suggestions to avoid infection which are still valid today.Sertürner was honoured by many institutions but still felt not properly esteemed. His behavior become odd and he debilitated. He died in 1841 and was buried in Einbeck.

The antinociceptive effect of the combination of spinal morphine with systemic morphine or buprenorphine.

UNLABELLED: We sought to analyze the mode of interaction of spinal morphine with systemic morphine or buprenorphine, administered in a wide range of antinociceptive doses. The study was performed on Sprague-Dawley rats by using a plantar stimulation test and isobolographic and fractional analyses of drug interaction. The isobolographic and fractional analyses demonstrated that intrathecal morphine interacted with subcutaneous morphine in a synergistic manner while producing a 50% or 75% antinociceptive effect. The sum of D(75) fractions was more than that for 50% antinociception, suggesting a less dramatic interaction. The combination with a maximal relative dose of systemic morphine (0.66:1) showed a maximal degree of supraadditivity. The interaction between spinal morphine and systemic buprenorphine was similar to that of morphine/morphine, although the supra-additivity was not as pronounced. For the doses that produced a 50% antinociceptive effect, a synergistic interaction was observed only for the combination with a morphine/buprenorphine ratio of 1.33:1. When the relative amount of intrathecal morphine was decreased or increased, the effect became additive. At the doses that produced 75% antinociception, both combinations of morphine and buprenorphine demonstrated supraadditive interaction. IMPLICATIONS: Spinal morphine interacts with systemic morphine or buprenorphine in asupraadditive manner. This mode of interaction most probably results from the simultaneous activation of spinal and supraspinal antinociceptive systems. Supraspinal structures played a more important role in the antinociceptive effect of experimental combinations than structures of the spinal cord.

Antinociceptive effect induced by the combined administration of spinal morphine and systemic buprenorphine.

UNLABELLED: We evaluated the antinociceptive effect of combined spinal administration of morphine and systemic administration of buprenorphine. Experiments were performed on male Wistar rats. Nociception was measured using the tail immersion test. Buprenorphine was injected intraperitoneally (IP) and morphine was injected intrathecally (IT) via a catheter implanted in the subarachnoid space. Interaction of drugs was analyzed using a dose addition model. Both IT (1-5 microg) morphine and IP (50-500 microg/kg) buprenorphine increased the latencies of nociceptive responses in a dose-dependent manner. IT morphine (4 microg) and IP buprenorphine (100 microg/kg) produced 62.9+/-6.3 and 48.8+/-6.6 percent of the maximal possible effect (%MPE), respectively. The combined administration of 2 microg of IT morphine and 50 microg/kg IP buprenorphine produced a %MPE of 97.1+/-3.4. The analysis of drug interaction revealed that IT morphine interacted with IP buprenorphine in a supraadditive manner while producing a potent antinociceptive effect. IMPLICATIONS: The concurrent administration of spinal morphine and systemic buprenorphine produces an antinociceptive effect that is greater than what could have been predicted from individual dose-response curves. This mode of interaction allows maintenance at a significant level of analgesia with reduced doses of opioids, which minimizes the incidence of undesirable side effects.

Depression of C fiber-evoked activity by intrathecally administered reactive red 2 in rat thalamic neurons.

To investigate the possible role of spinal purinoceptors in nociception, the potent P2-purinoceptor antagonist reactive red 2 was studied in rats under urethane anesthesia in which nociceptive activity was elicited by electrical stimulation of afferent C fibers in the sural nerve and recorded from single neurons in the ventrobasal complex of the thalamus. Intrathecal (i.t.) application of reactive red 2 (6-200 micrograms) caused a dose-dependent reduction of the evoked activity in thalamic neurons. The estimated ED50 was 30 micrograms, and the maximum depression of nociceptive activity amounted to about 70% of the control activity at a dose of 100 micrograms. Morphine, administered i.t. at a maximally effective dose (80 micrograms), inhibited the evoked nociceptive activity by only up to 55% of the control activity. An i.t. co-injection of reactive red 2 (100 micrograms) and morphine (80 micrograms) caused a maximum reduction of the evoked thalamic activity by up to 85% of the control activity, thus, exceeding significantly the effect elicited by either drug alone. Similarly, i.t. co-injection of almost equipotent dosages of reactive red 2 (30 micrograms) and morphine (30 micrograms) caused a maximum reduction of the evoked activity by up to 72% of the control activity, which again exceeded significantly the effect of either drug alone. The results suggest that in rats reactive red 2 exerts antinociception by blockade of P2-purinoceptors in the spinal cord and, hence, support the idea that ATP may play an important role in spinal transmission of nociceptive signals. An activation of the spinal opioid system does not seem to contribute to the effect of reactive red 2 but might act additive or even synergistically with its antinociceptive action.

[Analgesic and analgesia-potentiating action of B vitamins]. / Analgetische und analgesiepotenzierende Wirkung von B-Vitaminen.

Disregarding pain resulting from vitamin deficiency, an analgesic effect seems to be exerted only by vitamin B1 (thiamine), vitamin B6 (pyridoxines), and vitamin B12 (cobalamine), particularly when the three are given in combination. The analgesic effect is attributed to an increased availability and/or effectiveness of noradrenaline and 5-hydroxytryptamine acting as inhibitory transmitters in the nociceptive system. In animal experiments, high doses of these vitamins administered alone or in combination inhibited nociceptive behavior and depressed the nociceptive activity evoked in single neurons of the dorsal horn of the spinal cord and in the thalamus. Moreover, they were found to enhance the antinociceptive effect of non-opioid analgesic agents on withdrawal reflexes. Clinical data fail in most cases to meet current standards of evaluation (randomization, double-blindness). Still, it appears that high doses of the vitamins B1, B6, and B12 administered separately or in combination can alleviate acute pain and potentiate the analgesia caused by non-opioid analgesics such as the NSAIDs and metamizol (dipyrone). Therapeutic effects are observed in neuropathic pain and pain of musculoskeletal origin. Vitamin B6 is effective in the carpal tunnel syndrome which, however, is attributed at least in some cases to vitamin B6 deficiency. It is also worth noting that the B vitamins are shown to enhance the beneficial effect of diclofenac in acute low-back pain so that either the duration of treatment or the daily dose of diclofenac may be reduced. The use of high doses of vitamin B6 may be limited by a neurotoxic effect. The effectiveness of B vitamins in depressing chronic pain has not been established. It would be interesting to know if the B vitamins are of use as adjuvants in the treatment of tumor pain.

Analgesia by dihydrocodeine is not due to formation of dihydromorphine: evidence from nociceptive activity in rat thalamus.

Dihydrocodeine is increasingly used in slow-release preparations for the treatment of chronic pain on step 2 of the "analgesic ladder" of the World Health Organization. Dihydrocodeine is suggested to act after O-demethylation to dihydromorphine. To test this possibility, experiments were carried out on rats under urethane anesthesia in which nociceptive activity was evoked by electrical stimulation of afferent C fibers in the sural nerve and recorded from neurons in the ventrobasal complex of the thalamus. Dihydrocodeine administered by intravenous injection reduced the evoked nociceptive activity in a dose-dependent manner. Like morphine, dihydrocodeine was capable of completely suppressing the evoked activity. Maximum depression was caused by 2 mg/kg, and the ED50 is 0.47 mg/kg. Naloxone (0.2 mg/kg) reversed the effect of dihydrocodeine (2 mg/kg). To inhibit O-demethylation of dihydrocodeine to dihydromorphine, metyrapone or cimetidine (50 mg/kg) was injected intraperitoneally 20 min before dihydrocodeine (1 and 2 mg/kg). This failed to markedly reduce the effect of dihydrocodeine. Dihydromorphine injected intravenously also reduced the evoked activity in a dose-dependent way. Maximum depression occurred at a dose of 4 mg/kg, and the ED50 is 0.97 mg/kg. Dihydrocodeine and dihydromorphine were equieffective when administered by intrathecal injection at a dose of 100 microg. It is concluded that dihydrocodeine causes analgesia independent of biotransformation to dihydromorphine.

[Treament of morphine-induced constipation with oral naloxone]. / Aufhebung einer Morphin-induzierten Obstipation durch orales Naloxon.

INTRODUCTION: Almost all patients treated with opioids suffer from constipation. Numerous laxatives are used to overcome the problem, but none has yet been found to yield favourable results in all patients. Several studies have attempted to reverse opioid-induced constipation by the use of oral naloxone. Experiments carried out in rats showed that morphine-induced constipation is reduced by oral naloxone without impairment of antinociception [4]. However, evaluation of clinical studies reveals that there is uncertainty about the dosage regimen (the daily dose of naloxone ranged from 0.5% to about 60% that of morphine) and a lack of larger numbers of patients studied. METHODS: Fifteen patients suffering from opioid-induced constipation participated in the present study. Constipation had been present for 5 to 14 days despite the use of laxatives. According to the results obtained in the animal experiments [4], it was originally planned to administer oral naloxone at a dose ratio of 1:1 with respect to morphine on day 1 and 2; reducing it on day 3 and 4 to one-half and then to one-fourth of the initial dose on day 5 and 6. RESULTS: Twelve patients experienced a strong laxative effect with spontaneous bowel evacuation 1 to 4 h after the first intake of oral naloxone. Three patients had no laxative effects even after repeated doses. Eleven of the 15 patients reported an average loss of 10%-15% of analgesia after oral naloxone as measured by visual analogue scales. Increasing the morphine dose by about 15% restored the previous level of analgesia without reappearance of constipation. Eight of the 12 patients having a laxative effect experienced abdominal cramps, and therefore, the total dose of naloxone was reduced on day 2 to 2%-15% of that originally planned; this dose still produced a laxative effect. Four of the 15 patients had a withdrawal syndrome. A single dose of morphine equivalent to their daily morphine intake abolished the symptoms. DISCUSSION: The medical history of the 3 patients in whom naloxone failed to abolish constipation revealed neurological disturbances. Treatment of these patients included the use of neuroleptics, antiemetics, and other drugs. In this context, it should be noted that oral naloxone can be expected to abolish only opioid-induced constipation. In conclusion, it was found that the treatment of opioid-induced constipation by administration of oral naloxone produced positive results. A controlled study will show, whether the side effects can be minimized by reducing the naloxone dose.

Depression by morphine-6-glucuronide of nociceptive activity in rat thalamus neurons: comparison with morphine.

To assess the contribution of the active metabolite of morphine, morphine-6-glucuronide (M6G), to the analgesic effect of systemically administered morphine, experiments were carried out on rats under urethane anesthesia in which nociceptive activity was evoked by electrical stimulation of afferent C fibers in the sural nerve and recorded from single neurons in the ventrobasal complex of the thalamus. Intravenous (i.v.) injections of morphine completely blocked the activity at doses of 500 and 1000 micrograms/kg, the ED50 being 44 micrograms/kg. M6G administered by i.v. injection reduced the evoked nociceptive activity only by about 40% at 80 and 160 micrograms/kg, the ED50 being 6 micrograms/kg. After intrathecal (i.t.) injection, morphine produced maximum depression of 55% of the control activity at 20 micrograms; the ED50 is 18 micrograms. M6G injected i.t. produced maximum depression of 40% at doses ranging from 0.2 to 10 micrograms. The ED50 of M6G i.t. is below 0.2 micrograms. The effects of morphine and M6G were reversed by naloxone (200 micrograms/kg i.v.). The results show that M6G is more potent than morphine, regardless of the route of administration, while morphine is more effective when injected i.v. Due to the low efficacy of M6G, it seems unlikely that this glucuronide contributes substantially to the analgesic effect of morphine when renal function is normal. The results also make evident that the maximum effect of morphine results from an action at spinal and supraspinal sites.

[Oral papaverine prevents morphine-induced constipation without interfering with analgesia achieved with oral morphine]. / Orales Papaverin reduziert die morphinbedingte Obstipation ohne Abschwächung der Analgesie nach oralem Morphin.

Long-term administration of morphine for the treatment of chronic pain produces constipation; this requires the use of laxatives, which impair water absorption and upset the electrolyte balance. Morphine-induced constipation is mainly due to inhibition of the propulsive movement of the gastrointestinal tract combined with spastic contraction of smooth circular muscles as a result of drug binding to opioid receptors in the tract. Since papaverine lacks affinity for opioid receptors but relaxes smooth muscle, it seemed possible that oral papaverine might be capable of diminishing constipation without impairing the analgesia achieved with morphine. For this purpose, experiments were carried out on rats: constipation was checked for by measuring the intestinal transit time, and analgesia was assessed by measuring the latency of the tail-flick response to radiant heat or nociceptive activity in single neurons of the thalamus evoked by supramaximal electrical stimulation of afferent C fibres in the sural nerve. Morphine and papaverine were administered by the oral route. Control animals received saline. To measure the intestinal transit time, India ink solution was given orally. Morphine (2.5 and 5 mg/kg orally) prolonged the transit time from approx. 420 min in the controls to more than 600 min, a dose of 2.5 mg/kg producing the maximum effect. Papaverine (0.5, 1, and 2 mg/kg) administered orally together with morphine significantly reduced morphine-induced constipation (Tables 1, 2). Papaverine given alone at a dose of 2 mg/kg caused no change in transit time, while 5 mg/kg significantly increased it (Table 2). The latency of the tail-flick response was increased by oral morphine (2.5 and 5 mg/kg) at 1, 2, and 3 h after administration. Papaverine (0.5, 1 and 2 mg/kg) given in combination with morphine left the antinociceptive effect of morphine unchanged (Figs. 1-3). A study of the nociceptive activity evoked in thalamus neurons of rats under urethane anaesthesia indicated that intestinal absorption of morphine was blocked. Therefore, metoclopramide (0.15 mg/kg) was injected i. v. 10 min before oral administration of morphine or the combination of morphine plus papaverine. Subsequently, morphine produced a dose-dependent depression of evoked nociceptive activity (Fig. 4), the mean effect amounting to 60 % of the control activity and being produced by 2.5 mg/kg (Fig. 5). Since in former experiments on nociceptive activity evoked in thalamus neurones it has been found that the ED(50) of i. v. morphine is 0.05 mg/kg, it is very likely that the presystemic elimination of orally administered morphine is very high and, in addition, that the efficiency of its active metabolite, morphine-6-glucuronide, is rather poor. When morphine 2.5 mg/kg was given together with papaverine 0.5 mg/kg, and morphine 5 mg/kg was administered in combination with papaverine 2 mg/kg, there was no significant reduction in the depressant effect of morphine on nociceptive activity evoked in thalamus neurons (Figs. 6, 7). The results suggest that papaverine given by the oral route may reduce morphine-induced constipation without impairment of the analgesic action of morphine in patients suffering from pain.

[Antinociceptive effects of alpha(2)-adrenoceptor agonists ("analgesic" actions in animal experiments)agonists ("analgesic" actions in animal experiments).]. / Antinozizeptive Wirkungen von α(2)-Adrenozeptoragonisten ("analgetische" Wirkungen im Tierversuch)("analgetische" Wirkungen im Tierversuch).

alpha(2)-Adrenoceptor agonists like clonidine, dexmedetomidine, and ST-91, inhibit nociceptive reflex activity predominantly by a spinal mode of action. They mimic the action of the inhibitory transmitter noradrenaline, which is released from the terminals of bulbospinal monoaminergic pathways. The inhibition by noradrenaline is due partly to hyperpolarization of the postsynaptic neuronal membrane; however, the selective antinociceptive effect of the alpha(2)-adrenoceptor agonists results from reduction of the release of the excitatory transmitters such as glutamate and substance P, blockade of the binding of substance P to spinal neurones, and enhancement of the action of the inhibitory transmitter, 5-hydroxytryptamine. Clonidine and dexmedetomidine stimulate adrenoceptors of the alpha(2A) subtype, while ST-91 stimulates alpha(2B) adrenoceptors. Antinociception is manifested not only by depression of nociceptive reflexes and behaviour, but also by inhibition of the expression of immediate early genes in dorsal horn neurones following noxious stimulation. The inhibitory control from the brain stem of spinal nociceptive activity can be triggered by alpha(2)-adrenoceptor agonists. Moreover, impulse conduction in C fibres of peripheral nerves is far more reduced by these compounds than that in A fibres. Antinociceptive effects are reported to occur in various models of clinical pain, e.g. the formalin test, adjuvans-induced arthritis, autotomy following deafferentation, and "hyperalgesia" after nerve ligation. Therefore, the mechanisms involved in antinociception may also be responsible for the analgesia produced by alpha(2)-adrenoceptor agonists.

Depression by nicotine of pain-related nociceptive activity in the rat thalamus and spinal cord.

To assess the possible role of nicotinergic control in nociception and pain, experiments were carried out on rats under urethane anesthesia in which nociceptive activity was elicited by electrical stimulation of afferent C fibers in the sural nerve and recorded from single neurones in the thalamus and from ascending axons in the spinal cord. Intravenous administration of nicotine (0.01-0.5 mg/kg) depressed the nociceptive activity evoked in the thalamus and the spinal cord in a dose-dependent way. The maximum depression in thalamus and spinal cord was 40% of control activity and obtained at a dose of 0.025 mg/kg. Likewise, local administration of nicotine to the spinal cord by intrathecal injection (5, 10, and 30 micrograms) reduced the nociceptive activity evoked in neurones of the thalamus and in ascending axons of the spinal cord, the maximum of the depression being 40% of control activity. The depressant effect of nicotine (0.05 mg/kg) was reduced by mecamylamine (1 mg/kg) but not by atropine (0.5 mg/kg). It is concluded that the antinociceptive effect of nicotine is due to a specific action of the alcaloid at the spinal level.

[Oral administration of slow-release naloxone for prevention of constipation but not analgesia following oral morphine.]. / Retardiert freigesetztes Naloxon oral: Aufhebung der Obstipation durch orales Morphin ohne Beseitigung der Analgesie.

Prolonged administration of morphine for the treatment of chronic pain causes constipation requiring the use of laxatives, which may result in electrolyte deficits. Morphine-induced constipation is due to the binding of the drug to opioid receptors in the gastrointestinal tract and the brain, where it mimics the actions of enkephalins. The effect on the gastrointestinal tract seems to be more intense than the central effect. The particular pharmacokinetic of naloxone makes it possible to reduce or abolish the constipation that follows oral administration of morphine without markedly interfering with the central effect of morphine, i.e. analgesia. The results obtained with oral administration to rats of morphine and naloxone in aqueous solution have already been published [17]. Oral morphine in doses of 1, 2.5 and 5 mg/kg reduce the intestinal transit time in a dose-dependent manner (Fig. 2, filled circles). Doses of 10 and 20 mg/kg are as effective as 5 mg/kg. Naloxone 10 mg/kg administered together with morphine either prevented or attenuated the constipating effect of morphine (Fig. 2, open circles). Tail-flick latency was used as an indicator of analgesia in the animal experiment; it was significantly increased 1, 2 and 3 h after oral administration of morphine 2.5 mg/kg (Fig. 3, hatched columns). When naloxone 10 mg/kg was given with the morphine, there was no significant reduction in tail-flick latency (Fig. 3, cross-hatched columns). Thus, oral administration of naloxone in aqueous solution antagonized the constipating effect of morphine without interfering with the antinociceptive effect of morphine. Experiments carried out with oral administration to rats of slow-release naloxone instead of naloxone in aqueous solution have not so far been published. Slow-release naloxone 5 mg/kg abolished the slowing of intestinal transit caused by oral morphine 2.5 mg/kg (Fig. 4, left-hand columns). The increase in transit time following morphine 5 mg/kg was deminished by simultaneous oral administration of slow-release naloxone 3 and 5 mg/kg in a dose-dependent manner (Fig. 4, right-hand columns). The increase in tail-flick latency caused by morphine 2.5 mg/kg was reduced but not abolished by simultaneous administration of naloxone 5 mg/kg (Fig. 5). Slow-release naloxone 3 or 5 mg/kg reduced the duration without interfering with the maximum of the antinociceptive effect of morphine 5 mg/kg (Fig. 6). These results show that slow-release naloxone is more effective than naloxone in aqueous solution in antagonizing the effects of morphine: after oral administration of the slow-release preparation, even the central action of morphine is reduced. Provided that the anatomical organization of the haemorrhoidal veins in the rat is similar to that in man, slow-release naloxone will be carried by the matrix, to which it is absorbed further down in the gastrointestinal tract. It may thus even reach the rectum, from where, after having been absorbed, it bypasses the liver, enters the central nervous system and reduces the antinociceptive effect of morphine. In conclusion, it can be stated that oral administration of naloxone in combination with morphine may help to prevent constipation during the treatment of chronic pain.

[Labor pain-causes, pathways and issues.]. / Geburtsschmerz-Entstehung, Erregungsleitung und Folgen.

In the first stage of labor, pain is caused by distension of the cervix and low uterine segments in combination with isometric contraction of the uterus. Pain in the second stage of labor is dominated by tissue damage in the pelvis and perineum. Labor pain is due to an activation of nociceptors partly resulting from ischemia. The impulses thus generated are conducted into the spinal cord by afferent C fibers from the cervix and lower uterine segments, and by afferent Adelta and C fibers from the pelvis, pelvic organs and perineum. Labor pain is referred to the dermatomes T(11) and T(12) in the early stage of labor. It spreads to the neighboring dermatomes T(10) and L(1) and eventually involves the dermatomes S(2-4) during the second stage of labor and delivery. As in any other type of pain, labor pain stimulates respiration. This reduces the CO(2) concentration in the blood so that, in pain-free periods, respiratory stimulation is lacking and, in consequence, oxygen concentration in maternal and fetal blood is lowered. Pain-induced sympathetic activation will increase cardiac output in a way that may be deleterious in parturients with heart disease, eclampsia and anemia. Moreover, slowing of gastric emptying may cause nausea and vomiting, and slowing of intestinal propulsive movements may result in ileus and oliguria. An increase in plasma catecholamines and glucocorticoids influences uterine contractions. The amount of beta-endorphin released from the pituitary and placenta into the blood is relatively high but obviously not sufficient to depress pain effectively. Adequate nerve block and epidural anesthesia, as well as measures to relieve anxiety, will help markedly to reduce the risks associated with labor pain.

[NSAIDS in postoperative pain?]. / NSAR bei postoperativen Schmerzen?

Postoperative pain arises largely from distension and sectioning of nerve fibers, which generate a short-lasting but enormous afferent impulse barrage. This causes a long-lasting enlargement of receptive fields and an increase in excitability of dorsal horn neurons sending their axons up to the brain. The central process set up by extreme afferent excitation can be prevented by local anesthetics that will block afferent impulse conduction, or by premedication with opioid analgesics that will reduce the massive synaptic activation of dorsal horn neurons. Several mechanisms cause hyperactivity in these nociceptive neurons, one being an abundant formation of prostaglandins. Prostaglandins in the spinal cord facilitate the synaptic transmission from nociceptive afferents. Nonsteroidal anti-inflammatory drugs (NSAIDs) produce relief from postoperative pain by blocking the formation of prostaglandins in the spinal cord, thus abolishing the facilitatory effect of these compounds.

[How useful is the combination of B vitamins and analgesic agents?]. / Sind B-Vitamine sinnvolle Zusätze zu Analgetika? : Bericht über ein Symposium bei der 16. Jahrestagung der Deutschen Gesellschaft zum Studium des Schmerzes e.V., Berlin, 24.-27. Oktober 1991.

Vitamins of the B group have long been used to treat neuropathies of different origins and the accompanying pain. A combination of the vitamins B(1), B(6), and B(12) prevents the slowing of impulse conduction produced by tetanic stimulation in diabetic mice. In patients suffering from diabetic neuropathy, B vitamins alleviate pain in the upper extremities. Thermosensitivity is restored by B vitamins in the upper but not in the lower extremities. It has recently also been reported that a combination of the vitamins B1, B6, and B12 has analgesic properties in non-neuropathic conditions. In animal experiments, B vitamins diminish nociceptive responses in spinal and thalamic neurones and potentiate the antinociceptive effect of analgesic agents. Similarly, B vitamins potentiate the therapeutic effect of diclofenac in patients suffering from acute low back pain.

Oral naloxone reduces constipation but not antinociception from oral morphine in the rat.

Oral administration of naloxone (10 mg/kg) antagonized the slowing of the intestinal transit caused by oral morphine (1, 2.5 and 5 mg/kg) in rats. Oral administration of naloxone (10 mg/kg) did not prevent the antinociceptive effect of orally administered morphine (2.5 mg/kg) in the tail-flick test carried out on rats. It is concluded that oral naloxone locally blocks the constipating effect of morphine, while it fails to reduce the central action of morphine due to extensive metabolization after oral administration.

[Anticonvulsant agents in neuralgic pain.]. / Antikonvulsiva beim Nervenschmerz.

The anticonvulsants, carbamazepine, clonazepam, phenytoin, and valproic acid are capable of depressing attacks of shooting pain in neuralgia. Shooting pain is perceived in trigeminal, intercostal, and other neuralgias, as a consequence of infectious diseases such as herpes zoster, and in the course of polyneuropathies of various causes. It is due to injury of nociceptive afferents, which generate bursts of activity in response to appropriate environmental changes. The anticonvulsant agents have no analgesic property per se, so that background pain remains unchanged. The depression of shooting pain results from the anticonvulsant action of the compounds. Both carbamazepine and phenytoin block synaptic transmission of neuronal hyperactivity by a direct depressant action that includes reduction of sodium conductance and by activation of inhibitory control. Clonazepam and valproic acid act by enhancing GABA-mediated inhibition of synaptic transmission. Carbamazepine is by far the most widely used compound; phenytoin, clonazepam, and valproic acid are not so popular because of their side effects.

No psychological dependence after oral administration of morphine to rats.

Rats subjected to forced oral self-administration of morphine solutions without or in combination with two daily i.p. injections of morphine preferred drinking water when this was offered in addition to morphine solutions. The daily intake of morphine during the terminal phase of self-administration of morphine was 50-80 mg/kg (oral application alone) or 270 mg/kg (oral and i.p. application). Morphine treated animals showed withdrawal symptoms on administration of naloxone 1 mg/kg i.p. during the period of self-administration, but not when they had started drinking exclusively water. The tail-flick test revealed no tolerance during prolonged treatment with morphine. The results indicate that no psychological dependence developed when morphine was applied orally and regularly.