Anti-hyperalgesic effect of Lippia grata leaf essential oil complexed with ß-cyclodextrin in a chronic musculoskeletal pain animal model: Complemented with a molecular docking and antioxidant screening.

BACKGROUND: Due to its unclear pathophysiology, the pharmacological treatment of fibromyalgia is a challenge for researchers. Studies using medicinal plants, such as those from the genus Lippia, complexed with cyclodextrins (CDs) have shown innovative results. OBJECTIVE: The present research intended to evaluate the effect of an inclusion complex containing ß-cyclodextrin (ßCD) inclusion complex with Lippia grata (LG) essential oil in a chronic musculoskeletal pain model, its central activity and its possible interaction with neurotransmitters involved in pain. METHODS: After acid saline-induced chronic muscle pain, male mice were evaluated for primary and secondary hyperalgesia and muscle strength. Moreover, an antagonist assay was performed to assess the possible involvement of the opioidergic, serotonergic and noradrenergic pathways. In addition, Fos protein in the spinal cord was assessed, and a docking study and antioxidant assays were performed. RESULTS: The treatment with LG-ßCD, especially in the dose of 24mg/kg, was able to significantly decrease (p<0.05) the paw withdrawal and muscle threshold. Furthermore, LG-ßCD was shown to affect the opioidergic and serotonergic pathways. There were no significant changes in muscle strength. Fos protein immunofluorescence showed a significant decrease in expression in the dorsal horn of the spinal cord. The main compounds of LG showed through the docking study interaction energies with the alpha-adrenergic and µOpioid receptors. In all antioxidant assays, LG exhibited stronger antioxidant activities than LG-ßCD. CONCLUSION: This study suggested that LG-ßCD could be considered as a valuable source for designing new drugs in the treatment of chronic pain, especially musculoskeletal pain.

The role of methysergide in migraine and cluster headache treatment worldwide - A survey in members of the International Headache Society.

Background Methysergide has been as an effective treatment for migraine and cluster headache for over 50 years but has recently been investigated by the European Medicines Agency due to safety concerns. Methods To assess the need for continuing availability of methysergide, the International Headache Society performed an electronic survey among their members. Results The survey revealed that 71.3% of all respondents had ever prescribed methysergide and 79.8% would prescribe it if it were to become available. Respondents used it more in cluster headache than migraine, and reserved it for use in refractory patients. Conclusion The vast majority of headache experts in this survey regarded methysergide a unique treatment option for specific populations for which there are no alternatives, with an urgent need to continue its availability. This position was supported by the International Headache Society.

[Cluster headache treatment]. / Traitements de l'algie vasculaire de la face.

UNLABELLED: Acute treatment: sumatriptan, oxygen inhalation. Prophylactic treatment: verapamil, lithium carbonate. Transitional treatment. SURGICAL TREATMENT: deep brain stimulation, occipital nerve stimulation, stimulation of the sphenopalatin ganglion.

Involvement of transmitters in the anxiolytic action of urocortin 3 in mice.

Urocortin 3 (Ucn 3) was tested for anxiolytic action in mice an elevated plus maze. For detection of the possible involvement of neurotransmitters, the mice were pretreated with receptor blockers: haloperidol, phenoxybenzamine, propranolol, atropine, methysergide, bicuculline or naloxone. The peptide was administered into the lateral brain ventricle; the receptor blockers were applied intra- peritoneally. Ucn 3 alone elicited dose-dependent bell-shaped anxiolytic action. The most effective dose was 0.5 µg. In the combined testing a 0.5 µg dose was used. Haloperidol, propranolol, atropine, methysergide, and naloxone, blocked the Ucn 3-induced anxiolytic action, while phenoxybenzamine and bicuculline were ineffective. The results suggest that dopaminergic, beta-adrenergic, cholinergic, serotonergic and opiate transmissions are involved in the anxiolytic action of Ucn 3.

Role of 5-HT1B/1D receptors in the reduction of formalin-induced nociception and secondary allodynia/hyperalgesia produced by antimigraine drugs in rats.

AIMS: The present study analyzed the potential antinociceptive effect of the antimigraine drugs sumatriptan, dihydroergotamine or methysergide in rats submitted to the formalin test. Moreover, by using selective antagonists, the role of 5-HT1B/1D serotonergic receptors was investigated in the antinociception induced by these antimigraine drugs. MAIN METHODS: The formalin test was used to assess the nociceptive activity. Overt pain-like behavior (flinching, 1h) and evoked nociception (long-lasting secondary mechanical allodynia and hyperalgesia, 6 days) were determined in the same rat. KEY FINDINGS: Ipsilateral, but not contralateral, pre-treatment (in µg/paw) with sumatriptan (10-300), methysergide (1-30) or dihydroergotamine (1-30) significantly prevented flinching behavior (at 1h) as well as secondary allodynia and hyperalgesia (at day 6) induced by formalin. Interestingly, the antinociceptive (flinching), antiallodynic and antihyperalgesic effects of sumatriptan were completely prevented by peripheral pre-treatment with selective antagonists at the 5-HT1B (SB 224289; 100) or 5-HT1D (BRL 15572; 100) receptors. In contrast, the acute antinociceptive effects of methysergide and dihydroergotamine were partially prevented by SB 224289 and BRL 15572. The antiallodynic and antihyperalgesic effects of both drugs were completely prevented by BRL 15572 and partially prevented by SB 224289. Given alone, SB 224289 or BRL 15572 did not modify per se the long-lasting secondary allodynia and hyperalgesia. SIGNIFICANCE: The above findings suggest that: (i) the antimigraine drugs sumatriptan, methysergide and dihydroergotamine reduce the acute and chronic nociception induced by formalin; and (ii) this antinociceptive effect results from activation of peripheral 5-HT1B/1D serotonergic receptors.

Management of cluster headache.

The prevalence of cluster headache is 0.1% and cluster headache is often not diagnosed or misdiagnosed as migraine or sinusitis. In cluster headache there is often a considerable diagnostic delay - an average of 7 years in a population-based survey. Cluster headache is characterized by very severe or severe orbital or periorbital pain with a duration of 15-180 minutes. The cluster headache attacks are accompanied by characteristic associated unilateral symptoms such as tearing, nasal congestion and/or rhinorrhoea, eyelid oedema, miosis and/or ptosis. In addition, there is a sense of restlessness and agitation. Patients may have up to eight attacks per day. Episodic cluster headache (ECH) occurs in clusters of weeks to months duration, whereas chronic cluster headache (CCH) attacks occur for more than 1 year without remissions. Management of cluster headache is divided into acute attack treatment and prophylactic treatment. In ECH and CCH the attacks can be treated with oxygen (12 L/min) or subcutaneous sumatriptan 6 mg. For both oxygen and sumatriptan there are two randomized, placebo-controlled trials demonstrating efficacy. In both ECH and CCH, verapamil is the prophylactic drug of choice. Verapamil 360 mg/day was found to be superior to placebo in one clinical trial. In clinical practice, daily doses of 480-720 mg are mostly used. Thus, the dose of verapamil used in cluster headache treatment may be double the dose used in cardiology, and with the higher doses the PR interval should be checked with an ECG. At the start of a cluster, transitional preventive treatment such as corticosteroids or greater occipital nerve blockade can be given. In CCH and in long-standing clusters of ECH, lithium, methysergide, topiramate, valproic acid and ergotamine tartrate can be used as add-on prophylactic treatment. In drug-resistant CCH, neuromodulation with either occipital nerve stimulation or deep brain stimulation of the hypothalamus is an alternative treatment strategy. For most cluster headache patients there are fairly good treatment options both for acute attacks and for prophylaxis. The big problem is the diagnosis of cluster headache as demonstrated by the diagnostic delay of 7 years. However, the relatively short-lasting attack of pain in one eye with typical associated symptoms should lead the family doctor to suspect cluster headache resulting in a referral to a neurologist or a headache centre with experience in the treatment of cluster headache.

Neurotransmitter-mediated action of an antagonist of growth hormone-releasing hormone on anxiolysis in mice.

Antagonists of growth hormone-releasing hormone (GH-RH), such as MZ-4-71 suppress the secretion of GH. These findings suggest that GH-RH antagonists could be used for the therapy of disorders characterized by excessive GH secretion. It has been also demonstrated that MZ-4-71 displays antidepressant effects in a modified forced swimming test in mice, exerts anxiolytic effects in an elevated plus maze test, improves memory consolidation in passive avoidance learning, and corrects the impairment of memory consolidation caused by ß-amyloid (25-35) in mice. However, little is known about the mechanisms of action of MZ-4-71 on brain functions. In the present work, the involvement of the adrenergic, serotonergic and GABA-ergic receptors in the anxiolytic action of MZ-4-71 was studied in an elevated plus maze. Mice were pretreated with a nonselective α-adrenergic receptor antagonist, phenoxybenzamine, an α1/α2ß-adrenergic receptor antagonist, prazosin, an α2-adrenergic receptor antagonist, yohimbine, a mixed 5-HT1/5-HT2 serotonergic receptor antagonist, methysergide, a non-selective 5-HT2 serotonergic receptor antagonist, cyproheptadine, and a γ-aminobutyric acid subunit (GABA-A) receptor antagonist, bicuculline. Phenoxybenzamine, prazosin, yohimbine, methysergide, cyproheptadine and bicuculline prevented the effects of MZ-4-71 on the elevated plus maze revealing that the anxiolytic actions of MZ-4-71 in this test are mediated, at least in part, by the an interaction of the α1/α2-adrenergic, 5-HT1/5-HT2 serotonergic and GABA-A-ergic receptors.

Spinal segmental and supraspinal mechanisms underlying the pain-relieving effects of spinal cord stimulation: an experimental study in a rat model of neuropathy.

Spinal cord stimulation (SCS) may alleviate certain forms of neuropathic pain; its mechanisms of action are, however, not fully understood. Previous studies have mainly been focused onto segmental spinal mechanisms, though there is evidence indicating a supraspinal involvement. This study aims to evaluate the relative importance of segmental and supraspinal mechanisms related to the activation of the dorsal columns (DCs). Rats were used to induce the spared nerve injury neuropathy and simultaneously subjected to chronic bilateral DC lesions at the C6-C8 level. Two pairs of miniature electrodes were implanted in each animal, with a monopolar system placed in the dorsal epidural space at a low thoracic level (below lesion) and a bipolar system placed onto the dorsal column nuclei (above lesion). Stimulation (50 Hz, 0.2 ms, 2-4V, 5 min) was applied via either type of electrodes, and tests for sensitivity to tactile and thermal stimuli were used to assess its inhibitory effects. Various receptor antagonists {bicuculline (GABA(A)), saclofen (GABA(B)), ketanserine (5HT(2)), methysergide (5HT(1-2)), phentolamine (α-adrenergic), propranolol (ß-adrenergic), sulpiride (D(2)/D(3) dopamine) or saline were injected prior to the SCS. Rostral and caudal stimulations produced a comparable inhibition of neuropathic manifestations, and these effects were attenuated by about 50% after DC lesions. Pretreatment with the various receptor antagonists differentially influenced the effects of rostral and caudal stimulation. Our findings suggest that both supraspinal and segmental mechanisms are activated by SCS, and that in this model with DC lesions, rostral and caudal stimulations may activate different synaptic circuitries and transmitter systems.

What happens to the old headache medicines?

Old headache medicines never die; they either fade away or come back in disguise. The disguise is often a new route of administration, which may work better, faster, more completely, with fewer adverse events, and/or have certain other advantages. The clinical aspects of 3 of the oldest headache medicines (ergotamine tartrate, dihydroergotamine, and methysergide) will be discussed here. Sumatriptan will then be discussed as the prototype of the newest category of acute care therapy (triptans) for migraine. It will be compared with the older medications, and the new forms being developed will be briefly discussed. Diclofenac potassium for oral solution will be mentioned as the newest drug approved for migraine by the Food and Drug Administration, and a possible alternative to triptans in patients with frequent headaches or those with contraindications to vasoconstrictors.

Dihydroergotamine, ergotamine, methysergide and sumatriptan - basic science in relation to migraine treatment.

The 5-hydroxytryptamine (5-HT) receptor family mediates the effects of several drugs highly effective in migraine primarily by activating 5-HT(1B) , 5-HT(1D) , and 5-HT(1F) receptors. Ergotamine, dihydroergotamine, and methysergide, as well as the "triptan" sumatriptan, are all agonists for these receptors. The receptor profile and degree of selectivity of these four drugs differ, which is reflected by their side effects that limit their use in the acute and prophylactic treatment of migraine. The acute antimigraine efficacy of these remedies is very much dependent on the formulation used where, in general, parenteral formulations are more effective in reliving the symptoms of a migraine attack.

Headache currents commentary.

What Happens to the Old Headache Medicines? Rapoport AM, MD. Old headache medicines never die; they either fade away or come back in disguise. The disguise is often a new route of administration, which may work better, faster, more completely, with fewer adverse events, and/or have certain other advantages. The clinical aspects of 3 of the oldest headache medicines (ergotamine tartrate, dihydroergotamine, and methysergide) will be discussed here. Sumatriptan will then be discussed as the prototype of the newest category of acute care therapy (triptans) for migraine. It will be compared with the older medications, and the new forms being developed will be briefly discussed. Diclofenac potassium for oral solution will be mentioned as the newest drug approved for migraine by the Food and Drug Administration and a possible alternative to triptans in patients with frequent headaches or those with contraindications to vasoconstrictors. Dihydroergotamine, Ergotamine, Methysergide and Sumatriptan - Basic Science in Relation to Migraine Treatment. Dahlöf C, Maassen Van Den Brink A. The 5-hydroxytryptamine (5-HT) receptor family mediates the effects of several drugs highly effective in migraine primarily by activating 5-HT(1B) , 5-HT(1D) , and 5-HT(1F) receptors. Ergotamine, dihydroergotamine and methysergide, as well as the "triptan" sumatriptan, are all agonists for these receptors. The receptor profile and degree of selectivity of these 4 drugs differ, which is reflected by their side effects that limit their use in the acute and prophylactic treatment of migraine. The acute antimigraine efficacy of these remedies is very much dependent on the formulation used where, in general, parenteral formulations are more effective in relieving the symptoms of a migraine attack.

[Preventive medication in migraine headache : Individualized clinical pathways]. / Medikamentöse Prophylaxe der Migräne : Individuelle Behandlungspfade.

With the introduction of the highly effective triptans in the treatment of acute migraine attacks, the significance of migraine prevention temporarily lost ground in the awareness of doctors and, even more so, patients. This was unjustified, as the increasing numbers of patients with triptan-overuse headache clearly demonstrated. Recent years have seen this trend reversed with a resurgence of migraine prevention. In daily practice the first question is whether migraine prevention is indeed indicated for the patient. If answered affirmatively, the next step is the intricate selection of the most promising agent for the patient. Treatment guidelines regularly updated by the relevant medical societies provide a general overview of the agents principally available according to the principles of evidence-based medicine. Yet, low compliance rates suggest that in practice implementation of these guidelines may have to be tailored to the patient in question. The treatment algorithm presented here tries to bridge the gulf between general treatment guidelines and the actual needs of the patient. From this, feasible clinical pathways are derived for individualized treatment.

History of methysergide in migraine.

Harold Wolff's theory of vasodilation in migraine is well-known. Less known is his search for a perivascular factor that would damage local tissues and increase pain sensitivity during migraine attacks. Serotonin was found to be among the candidate agents to be included. In the same period, serotonin was isolated (1948) and, because of its actions, an anti-serotonin drug was needed. Methysergide was synthesized from lysergic acid (LSD) by adding a methyl group and a butanolamid group. This resulted in a compound with selectivity and high potency as a serotonin (5-HT) inhibitor. Based on the possible involvement of serotonin in migraine attacks, it was introduced in 1959 by Sicuteri as a preventive drug for migraine. The clinical effect was often excellent, but 5 years later it was found to cause retroperitoneal fibrosis after chronic intake. Consequently, the use of the drug in migraine declined considerably, but it was still used as a 5-HT antagonist in experimental studies. In 1974 Saxena showed that methysergide had a selective vasoconstrictor effect in the carotid bed and in 1984 he found an atypical receptor. This finding provided an incentive for the development of sumatriptan. Bredberg et al. showed that methysergide is probably a prodrug for its active metabolite methylergometrine. Whereas methysergide is 'a clean drug', methylergometrine is 'a relatively dirty drug' with additional dopaminergic activity. The mechanism for the preventive effect of methysergide (methylergometrine) in migraine remains elusive. We describe the rise, fall and subsequent use as a third-choice drug of the first effective migraine prophylactic, methysergide.

[Pathophysiology and treatment of trigeminal autonomic cephalalgias]. / Neues zur Pathophysiologie und Therapie der trigeminoautonomen Kopfschmerzsyndrome.

Trigeminal autonomic cephalalgias (TACs) are a group of primary headache disorders, which are characterized by strictly unilateral pain, together with ipsilateral cranial autonomic symptoms. TACs include cluster headache (CH), paroxysmal hemicrania (PH) and short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT syndrome). These diseases all have one thing in common: an activation of trigeminal nociceptive afferentia with a reflex-like activation of cranial autonomic efferentia via the facial nerve. TACs show differences not only in the length and frequency of attacks but also in the response to drug treatment. It is important to recognize and differentiate between these syndromes because they react very well, but very selectively to therapy.

Interference of methysergide, a specific 5-hydroxytryptamine receptor antagonist, with airway chronic allergic inflammation and remodelling in a murine model of asthma.

BACKGROUND: Airway remodelling encompasses the structural changes observed in asthmatic airways. Mast cells, through the release of histamine and 5-hydroxytryptamine (serotonin), are implicated in early asthmatic reactions, bronchoconstriction and mucosal oedema, and in the development of bronchial hyperresponsiveness. However, the association between serotonin and remodelling processes in murine model of airways inflammation remains to be elucidated. OBJECTIVE: As serotonin is released by murine mast cells upon antigen challenge, we tested the hypothesis of its involvement in the development of inflammatory and remodelling processes in a murine model of chronic airway inflammation following prolonged allergen challenge. Methods BALB/c mice were exposed to aerosolized ovalbumin for 20 min 2 days a week, for 4 consecutive weeks. Two hours before each challenge, they were treated with methysergide (intranasally, 40 microg/kg). Forty-eight hours after the last aerosol challenge, bronchoalveolar lavage (BAL) and lung tissue were collected for analysis. RESULTS: Methysergide inhibited the allergen-induced increase in airway eosinophilia, reduced T helper type 2 (Th2) cytokines in lung, spleen or thoracic lymph nodes, and specific IgE levels. The extravasation of plasma and fibronectin production in the lung, and collagen deposition in the lung were also inhibited after methysergide treatment. Although methysergide treatment induced an increase in IFN-gamma levels, experiments with neutralizing antibody suggest that this is not responsible for inhibition. In addition, instillation of serotonin to immunized mice induced eosinophil recruitment to BAL, Th2 cytokine production and fibronectin release in lung as well as collagen deposition. CONCLUSION: Serotonin may contribute to the development and maintenance of remodelling through the release of cytokines and of fibrogenic mediators. Serotonin should therefore be considered as relevant for the development and maintenance of airway remodelling.

Pharmacological prevention of migraine: to be considered case by case.

(1) Migraines are characterized by recurrent headaches generally lasting between 4 and 72 hours and disappearing without complication. They can be incapacitating, owing to their frequency and/or intensity. (2) Many drugs have been used to prevent migraines. One of the most common outcome measures used in clinical trials is the proportion of responder patients, defined as those in whom the monthly frequency of migraines is at least halved. On average, about one-third of patients respond to placebo in clinical trials. (3) Propranolol is the betablocker with the best-documented efficacy: in absolute terms the response rate is about 30% higher than with placebo. The adverse effects of betablockers are mainly cardiovascular and neuropsychological. (4) Valproic acid, an anticonvulsant, is about as effective as propranolol, and its adverse effects are generally acceptable. (5) Amitriptyline is the antidepressant with the best-documented preventive effects, with a response rate about 20% higher than placebo. Its principal adverse effects are due to its atropinic action. Amitriptyline can also have a sedative effect. (6) Flunarizine also has documented efficacy, but this "hidden neuroleptic" can cause extrapyramidal disorders and weight gain. (7) Among the serotonergic antagonists, methysergide has documented efficacy but long-term treatment can lead to serious retroperitoneal, pulmonary or cardiac fibrosis. Pizotifen causes drowsiness or weight gain in about 50% of patients. (8) The choice of preventive treatment for migraine must be based on the balance between efficacy (compared to placebo) and adverse effects. In practice, the first choice drug is propranolol. (9) Because the frequency of migraines fluctuates over time, withdrawal of prophylaxis should be attempted on a regular basis, with the patient's consent.

EFNS guidelines on the treatment of cluster headache and other trigeminal-autonomic cephalalgias.

Cluster headache and the other trigeminal-autonomic cephalalgias [paroxysmal hemicrania, short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) syndrome] are rare but very disabling conditions with a major impact on the patient's quality of life. The objective of this study was to give evidence-based recommendations for the treatment of these headache disorders based on a literature search and consensus amongst a panel of experts. All available medical reference systems were screened for any kind of studies on cluster headache, paroxysmal hemicrania and SUNCT syndrome. The findings in these studies were evaluated according to the recommendations of the European Federation of Neurological Societies resulting in level A, B or C recommendations and good practice points. For the acute treatment of cluster headache attacks, oxygen (100%) with a flow of at least 7 l/min over 15 min and 6 mg subcutaneous sumatriptan are drugs of first choice. Prophylaxis of cluster headache should be performed with verapamil at a daily dose of at least 240 mg (maximum dose depends on efficacy or tolerability). Although no class I or II trials are available, steroids are clearly effective in cluster headache. Therefore, the use of at least 100 mg methylprednisone (or equivalent corticosteroid) given orally or at up to 500 mg i.v. per day over 5 days (then tapering down) is recommended. Methysergide, lithium and topiramate are recommended as alternative treatments. Surgical procedures, although in part promising, require further scientific evaluation. For paroxysmal hemicranias, indomethacin at a daily dose of up to 225 mg is the drug of choice. For treatment of SUNCT syndrome, large series suggest that lamotrigine is the most effective preventive agent, with topiramate and gabapentin also being useful. Intravenous lidocaine may also be helpful as an acute therapy when patients are extremely distressed and disabled by frequent attacks.

State of the science: hot flashes and cancer. Part 2: management and future directions.

PURPOSE/OBJECTIVES: To critically evaluate and synthesize intervention research related to hot flashes in the context of cancer and to identify implications and future directions for policy, research, and practice. DATA SOURCES: Published, peer-reviewed articles and textbooks; editorials; and computerized databases. DATA SYNTHESIS: Although a variety of pharmacologic and nonpharmacologic treatments are available, they may not be appropriate or effective for all individuals. CONCLUSIONS: The large and diverse evidence base and current national attention on hot flash treatment highlight the importance of the symptom to healthcare professionals, including oncology nurses. IMPLICATIONS FOR NURSING: Using existing research to understand, assess, and manage hot flashes in the context of cancer can prevent patient discomfort and improve the delivery of evidence-based care.

Psychiatric side effects during methysergide treatment.

A patient is reported with psychological change characterised by impaired concentration and thought projection, followed by both severe anxiety and depression, starting after three weeks on high dose methysergide. The acute problem settled slowly after methysergide withdrawal and is likely to represent an unusual and serious side effect of that drug.

Centrally active nonhormonal hot flash therapies.

Given the problems associated with hormonal therapy, and the prominent problem of hot flashes in menopausal women, there is a need for nonhormonal agents to alleviate hot flashes. Several compounds that appear to act on the central nervous system have been investigated. Potential mechanisms for their effects on hot flashes have been described. Bellergal (no longer available on the US market, where it was known as Bellergal-S), a combination preparation sedative that consists of low-dose phenobarbital, ergotamine tartrate, and levorotatory alkaloids of belladonna, is an old agent that was popular approximately 20 years ago; however, there is limited suggestion of efficacy for this agent. Clonidine, an older antihypertensive drug, is another centrally active agent that has been studied. Randomized trials have demonstrated that it clearly works for reducing hot flashes, but the magnitude of efficacy is somewhat limited. Toxicity from this agent limits its utility in the clinic. Methyldopa is another centrally active agent that has been studied but to a more limited degree. It appears to have minimal efficacy and too much toxicity to make it clinically useful. Anecdotal observations from a number of sources suggested that newer antidepressants can alleviate hot flashes. This led to pilot trials of venlafaxine and paroxetine, with results suggesting benefit from both drugs. Subsequently, randomized, placebo-controlled, double-blind clinical trials of venlafaxine, paroxetine, and fluoxetine were conducted. All 3 of these clinical trials demonstrated statistically significant reductions in hot flashes with these newer antidepressants compared with placebo. Pilot trials of citalopram and mirtazapine, 2 other newer antidepressants, have also suggested efficacy. Toxicity evaluations have suggested that these agents are, again, well tolerated by the majority of patients. A recent trial, however, was unable to demonstrate any benefit for fluoxetine or citalopram over a placebo. Anecdotal observations also suggested that gabapentin was helpful for alleviating hot flashes. This led to pilot trials that again suggested efficacy. Subsequently, 2 large placebo-controlled, randomized, double-blind clinical trials were conducted. Both of these demonstrated statistically significant efficacy for gabapentin compared with a placebo. This drug is relatively well tolerated by most patients. Thus, centrally active nonhormonal agents clearly do decrease hot flashes in women. The most efficacious and clinically appropriate agents for use are newer antidepressants and gabapentin. Continued evaluation of the efficacy and toxicity of these agents is ongoing.