Benzodiazepine withdrawal syndrome

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https://en.wikipedia.org/wiki/Benzodiazepine_withdrawal_syndrome 

 

Benzodiazepine withdrawal syndrome
Other names	Benzo withdrawal
Diazepam is sometimes used in the treatment of benzodiazepine withdrawal.
Specialty	Psychiatry

Benzodiazepines
The core structure of benzodiazepines. "R" labels denote common locations of side chains, which give different benzodiazepines their unique properties.
Pronunciation: /ˌbɛnzoʊdaɪˈæzəpiːn/ Benzodiazepine List of benzodiazepines Benzodiazepine overdose Benzodiazepine dependence Benzodiazepine misuse Benzodiazepine withdrawal syndrome Effects of long-term benzodiazepine use

Benzodiazepine withdrawal syndrome—often abbreviated to benzo withdrawal or BZD withdrawal —is the cluster of signs and symptoms that emerge when a person who has been taking benzodiazepines, either medically or recreationally, and has developed a physical dependence, undergoes dosage reduction or discontinuation. Development of physical dependence and the resulting withdrawal symptoms, some of which may last for years, may result from taking the medication as prescribed. Benzodiazepine withdrawal is characterized by sleep disturbance, irritability, increased tension and anxiety, panic attacks, hand tremor, shaking, sweating, difficulty with concentration, confusion and cognitive difficulty, memory problems, dry retching and nausea, weight loss, palpitations, headache, muscular pain and stiffness, a host of perceptual changes, hallucinations, seizures, psychosis, and increased risk of suicide (see "signs and symptoms" section below for full list). Further, these symptoms are notable for the manner in which they wax and wane and vary in severity from day to day or week by week instead of steadily decreasing in a straightforward monotonic manner. This phenomenon is often referred to as "waves" and "windows".

It is a potentially serious condition, and is complex and often protracted in its course. Long-term benzodiazepine use, defined as daily use for at least three months, is not desirable because of the associated increased risk of dependence, dose escalation, loss of efficacy, increased risk of accidents and falls, particularly for the elderly, as well as cognitive, neurological, and intellectual impairments. Use of short-acting hypnotics, while being effective at initiating sleep, worsens the second half of sleep due to withdrawal effects.

Benzodiazepine withdrawal can be severe and can provoke life-threatening withdrawal symptoms, such as seizures, particularly with abrupt or overly rapid dosage reduction from high doses or long-time use. A severe withdrawal response can nevertheless occur despite gradual dose reduction, or from relatively low doses in short-time users; even after a single large dose in animal models. A minority of individuals will experience a protracted withdrawal syndrome, whose symptoms may persist at a sub-acute level for months or years after cessation of benzodiazepines. The likelihood of developing a protracted withdrawal syndrome can be minimized by a slow, gradual reduction in dosage.

Chronic exposure to benzodiazepines causes neural adaptations that counteract the drug's effects, leading to tolerance and dependence. Despite taking a constant therapeutic dose, long-term use of benzodiazepines may lead to the emergence of withdrawal-like symptoms, particularly between doses, when patients are treated with shorter-acting benzodiazepines. When the drug is discontinued or the dosage reduced, withdrawal symptoms may appear and remain until the body has reversed the long-term physiological adaptations. These [[Rebound effect|rebound symptoms may be identical to the symptoms for which the drug was initially taken, or may be part of discontinuation symptoms. In severe cases, the withdrawal reaction may exacerbate or resemble serious psychiatric and medical conditions, such as mania, schizophrenia, and, especially at high doses, seizure disorders. Failure to recognize discontinuation symptoms can lead to false evidence for the need to take benzodiazepines, which in turn leads to withdrawal failure and reinstatement of benzodiazepines, often at higher doses.

Awareness of the withdrawal reactions, individualized taper strategies according to withdrawal severity, the addition of alternative strategies such as reassurance and referral to benzodiazepine withdrawal support groups, all increase the success rate of withdrawal.

Signs and symptoms

Withdrawal effects caused by sedative-hypnotics discontinuation, such as benzodiazepines, barbiturates, or alcohol, can cause serious medical complications. They are cited to be more hazardous to withdraw from than opioids. Users typically receive little advice and support for discontinuation. Some withdrawal symptoms are identical to the symptoms for which the medication was originally prescribed, and can be acute or protracted in duration. Onset of symptoms from long half-life benzodiazepines might be delayed for up to three weeks, although withdrawal symptoms from short-acting ones often present early, usually within 24–48 hours. There may be no fundamental differences in symptoms from either high or low dose discontinuation, but symptoms tend to be more severe from higher doses.

Daytime reemergence and rebound withdrawal symptoms, sometimes confused with interdose withdrawal, may occur once dependence has set in. 'Reemergence' is the return of symptoms for which the drug was initially prescribed, in contrast, 'rebound' symptoms are a return of the symptoms for which the benzodiazepine was initially taken, but at a more intense level than before; whereas 'interdose withdrawal' is when a prior dosage of drug wears off and beginnings of an entirely new cycle of withdrawal sets in, the symptoms of which dissipate upon taking the next dosage but after which yet another entirely new cycle of withdrawal begins when that dosage wears off, a new onset of withdrawal between each dosage thus called 'interdose withdrawal' and if not properly treated can recur indefinitely in a vicious circle (for which a benzo with a long half life, e.g. diazepam, can be substituted so the drug does not wear off between doses).

Withdrawal symptoms may appear for the first time during dose reduction, and include insomnia, anxiety, distress, weight loss, dizziness, night sweats, shakes, muscle twitches, aphasia, panic attacks, depression, derealization, paranoia, indigestion, diarrhea, photo phobia etc., and are more commonly associated with short-acting benzodiazepines discontinuation, like triazolam. Daytime symptoms can occur after a few days to a few weeks of administration of nightly benzodiazepines or z-drugs such as zopiclone; withdrawal-related insomnia rebounds worse than baseline, and for rapidly eliminated benzodiazepines, including triazolam and temazepam, this may occur even when used briefly and intermittently, according to a small 1991 study (n=18).

The following symptoms may emerge during gradual or abrupt dosage reduction:

• Akathisia
• Agitation and anxiety, possible terror and panic attacks
• Blurred vision
• Chest pain
• Depersonalization and derealisation (feelings of unreality)
• Depression (can be severe), possible suicidal ideation
• Dilated pupils
• Dizziness
• Dry mouth
• Dysphoria
• Elevation in blood pressure
• Fatigue and weakness
• Gastrointestinal disturbance (including nausea, diarrhea, vomiting)
• Hearing disturbance
• Headache
• Hot and cold spells
• Hyperosmia
• Hyperacusis
• Hypertension
• Hypnagogic hallucinations
• Hypochondriasis
• Increased sensitivity to touch
• Increased urinary frequency
• Insomnia
• Impaired memory and concentration
• Loss of appetite and weight loss
• Mild to moderate aphasia
• Mood swings
• Muscular spasms, cramps, discomfort or fasciculations
• Nightmares
• Obsessive compulsive disorder
• Paraesthesia
• Paranoia
• Perspiration
• Photophobia
• Postural hypotension
• REM sleep rebound
• Restless legs syndrome
• Stiffness
• Taste and smell disturbances
• Tachycardia
• Tinnitus
• Tremor
• Visual disturbances

Rapid discontinuation may result in a more serious syndrome

• Catatonia, which may result in death
• Confusion
• Convulsions, which may result in death
• Coma (rare)
• Delirium tremens
• Hyperthermia
• Mania
• Neuroleptic malignant syndrome-like event (rare)
• Organic brain syndrome
• Post-traumatic stress disorder
• Psychosis
• Suicidal ideation or suicide
• Violence and aggression

As withdrawal progresses, patients often find their physical and mental health improves with improved mood and improved cognition.

Mechanism

The neuroadaptive processes involved in tolerance, dependence, and withdrawal mechanisms implicate both the GABAergic and the glutamatergic systems. Gamma-Aminobutyric acid (GABA) is the major inhibitory neurotransmitter of the central nervous system; roughly one-quarter to one-third of synapses use GABA. GABA mediates the influx of chloride ions through ligand-gated chloride channels called GABA_A receptors. When chloride enters the nerve cell, the cell membrane potential hyperpolarizes thereby inhibiting depolarization, or reduction in the firing rate of the post-synaptic nerve cell. Benzodiazepines potentiate the action of GABA, by binding a site between the α and γ subunits of the 5-subunit receptor thereby increasing the frequency of the GABA-gated chloride channel opening in the presence of GABA.

When potentiation is sustained by long-term use, neuroadaptations occur which result in decreased GABAergic response. What is certain is that surface GABA_A receptor protein levels are altered in response to benzodiazepine exposure, as is receptor turnover rate. The exact reason for the reduced responsiveness has not been elucidated but down-regulation of the number of receptors has only been observed at some receptor locations including in the pars reticulata of the substantia nigra; down-regulation of the number of receptors or internalization does not appear to be the main mechanism at other locations. Evidence exists for other hypotheses including changes in the receptor conformation, changes in turnover, recycling, or production rates, degree of phosphorylation and receptor gene expression, subunit composition, decreased coupling mechanisms between the GABA and benzodiazepine site, decrease in GABA production, and compensatory increased glutamatergic activity. A unified model hypothesis involves a combination of internalization of the receptor, followed by preferential degradation of certain receptor sub-units, which provides the nuclear activation for changes in receptor gene transcription.

It has been postulated that when benzodiazepines are cleared from the brain, these neuroadaptations are "unmasked", leading to unopposed excitability of the neuron. Glutamate is the most abundant excitatory neurotransmitter in the vertebrate nervous system. Increased glutamate excitatory activity during withdrawal may lead to sensitization or kindling of the CNS, possibly leading to worsening cognition and symptomatology and making each subsequent withdrawal period worse. Those who have a prior history of withdrawing from benzodiazepines are found to be less likely to succeed the next time around.

Diagnosis

In severe cases, the withdrawal reaction or protracted withdrawal may exacerbate or resemble serious psychiatric and medical conditions, such as mania, schizophrenia, agitated depression, panic disorder, generalised anxiety disorder, and complex partial seizures and, especially at high doses, seizure disorders. Failure to recognize discontinuation symptoms can lead to false evidence for the need to take benzodiazepines, which in turn leads to withdrawal failure and reinstatement of benzodiazepines, often to higher doses. Pre-existing disorder or other causes typically do not improve, whereas symptoms of protracted withdrawal gradually improve over the ensuing months.

Symptoms may lack a psychological cause and can fluctuate in intensity with periods of good and bad days until eventual recovery.

Prevention

According to the British National Formulary, it is better to withdraw too slowly rather than too quickly from benzodiazepines. The rate of dosage reduction is best carried out so as to minimize the symptoms' intensity and severity. Anecdotally, a slow rate of reduction may reduce the risk of developing a severe protracted syndrome.

Long half-life benzodiazepines like diazepam or chlordiazepoxide are preferred to minimize rebound effects and are available in low dose forms. Some people may not fully stabilize between dose reductions, even when the rate of reduction is slowed. Such people sometimes simply need to persist as they may not feel better until they have been fully withdrawn from them for a period of time.

Management

Chlordiazepoxide, 5 mg capsules, are sometimes used as an alternative to diazepam for benzodiazepine withdrawal. Like diazepam, it has a long elimination half-life and long-acting active metabolites.

Management of benzodiazepine dependence involves considering the person's age, comorbidity and the pharmacological pathways of benzodiazepines. Psychological interventions may provide a small but significant additional benefit over gradual dose reduction alone at post-cessation and at follow-up. The psychological interventions studied were relaxation training, cognitive-behavioral treatment of insomnia, and self-monitoring of consumption and symptoms, goal-setting, management of withdrawal and coping with anxiety.

There is no standard approach to managing benzodiazepine withdrawal. With sufficient motivation and the proper approach, almost anyone can successfully withdraw from benzodiazepines. However, a prolonged and severe syndrome can lead to collapsed marriages, business failures, bankruptcy, hospitalization, and the most serious adverse effect, suicide. As such, long-term users should not be forced to discontinue against their will.

Over-rapid withdrawal, lack of explanation, and failure to reassure individuals that they are experiencing temporary withdrawal symptoms led some people to experience increased panic and fears they are going mad, with some people developing a condition similar to post-traumatic stress disorder as a result. A slow withdrawal regimen, coupled with reassurance from family, friends, and peers improves the outcome. According to a 2015 Cochrane review, cognitive behavior therapy plus taper was effective in achieving discontinuation in the short-term but the effect was not certain after six months.

Medications

While some substitutive pharmacotherapies may have promise, current evidence is insufficient to support their use. Some studies found that the abrupt substitution of substitutive pharmacotherapy was actually less effective than gradual dose reduction alone, and only three studies found benefits of adding melatonin, paroxetine, trazodone, or valproate in conjunction with a gradual dose reduction.

• Antipsychotics are generally ineffective for benzodiazepine withdrawal-related psychosis. Antipsychotics should be avoided during benzodiazepine withdrawal as they tend to aggravate withdrawal symptoms, including convulsions. Some antipsychotic agents may be riskier than others during withdrawal, especially clozapine, olanzapine or low potency phenothiazines (e.g., chlorpromazine), as they lower the seizure threshold and can worsen withdrawal effects; if used, extreme caution is required.
• Barbiturates are cross tolerant to benzodiazepines and should generally be avoided; however phenobarbital can be used, as it is relatively safe, see below.
• Benzodiazepines or cross tolerant drugs should be avoided after discontinuation, even occasionally. These include the nonbenzodiazepines Z-drugs, which have a similar mechanism of action. This is because tolerance to benzodiazepines has been demonstrated to be still present at four months to two years after withdrawal depending on personal biochemistry. Re-exposures to benzodiazepines typically resulted in a reactivation of the tolerance and benzodiazepine withdrawal syndrome.
• Bupropion, which is used primarily as an antidepressant and smoking cessation aid, is contraindicated in persons experiencing abrupt withdrawal from benzodiazepines or other sedative-hypnotics (e.g. alcohol), due to an increased risk of seizures.
• Buspirone augmentation was not found to increase the discontinuation success rate.
• Caffeine may worsen withdrawal symptoms because of its stimulatory properties. At least one animal study has shown some modulation of the benzodiazepine site by caffeine, which produces a lowering of seizure threshold.
• Carbamazepine, an anticonvulsant, appears to have some beneficial effects in the treatment and management of benzodiazepine withdrawal; however, research is limited and thus the ability of experts to make recommendations on its use for benzodiazepine withdrawal is not possible at present.
• Ethanol, the primary alcohol in alcoholic beverages, even mild to moderate use, has been found to be a significant predictor of withdrawal failure, probably because of its cross tolerance with benzodiazepines.
• Flumazenil has been found to stimulate the reversal of tolerance and the normalization of receptor function. However, further research is needed in the form of randomised trials to demonstrate its role in the treatment of benzodiazepine withdrawal. Flumazenil stimulates the up-regulation and reverses the uncoupling of benzodiazepine receptors to the GABA_A receptor, thereby reversing tolerance and reducing withdrawal symptoms and relapse rates. Because of limited research and experience compared to the possible risks involved, the flumazenil detoxification method is controversial and can only be done as an inpatient procedure under medical supervision.

Flumazenil was found to be more effective than placebo in reducing feelings of hostility and aggression in patients who had been free of benzodiazepines for 4–266 weeks. This may suggest a role for flumazenil in treating protracted benzodiazepine withdrawal symptoms.

A study into the effects of the benzodiazepine receptor antagonist, flumazenil, on benzodiazepine withdrawal symptoms persisting after withdrawal was carried out by Lader and Morton. Study subjects had been benzodiazepine-free for between one month and five years, but all reported persisting withdrawal effects to varying degrees. Persistent symptoms included clouded thinking, tiredness, muscular symptoms such as neck tension, depersonalisation, cramps and shaking and the characteristic perceptual symptoms of benzodiazepine withdrawal, namely, pins and needles feeling, burning skin, pain and subjective sensations of bodily distortion. Therapy with 0.2–2 mg of flumazenil intravenously was found to decrease these symptoms in a placebo-controlled study. This is of interest as benzodiazepine receptor antagonists are neutral and have no clinical effects. The author of the study suggested the most likely explanation is past benzodiazepine use and subsequent tolerance had locked the conformation of the GABA-BZD receptor complex into an inverse agonist conformation, and the antagonist flumazenil resets benzodiazepine receptors to their original sensitivity. Flumazenil was found in this study to be a successful treatment for protracted benzodiazepine withdrawal syndrome, but further research is required. A study by Professor Borg in Sweden produced similar results in patients suffering from protracted withdrawal. In 2007, Hoffmann–La Roche the makers of flumazenil, acknowledged the existence of protracted benzodiazepine withdrawal syndromes, but did not recommended flumazenil to treat the condition.

• Fluoroquinolone antibiotics have been noted to increase the incidence of a CNS toxicity from 1% in the general population, to 4% in benzodiazepine-dependent population or in those undergoing withdrawal from them. This is probably the result of their GABA antagonistic effects as they have been found to competitively displace benzodiazepines from benzodiazepine receptor sites. This antagonism can precipitate acute withdrawal symptoms, that can persist for weeks or months before subsiding. The symptoms include depression, anxiety, psychosis, paranoia, severe insomnia, paresthesia, tinnitus, hypersensitivity to light and sound, tremors, status epilepticus, suicidal thoughts and suicide attempt. Fluoroquinolone antibiotics should be contraindicated in patients who are dependent on or in benzodiazepine withdrawal. NSAIDs have some mild GABA antagonistic properties and animal research indicate that some may even displace benzodiazepines from their binding site. However, NSAIDs taken in combination with fluoroquinolones cause a very significant increase in GABA antagonism, GABA toxicity, seizures, and other severe adverse effects.
• Imidazenil has received some research for management of benzodiazepine withdrawal, but is not currently used in withdrawal.
• Imipramine was found to statistically increase the discontinuation success rate.
• Melatonin augmentation was found to statistically increase the discontinuation success rate for people with insomnia.
• Phenobarbital, (a barbiturate), is used at "detox" or other inpatient facilities to prevent seizures during rapid withdrawal or cold turkey. The phenobarbital is followed by a one- to two-week taper, although a slow taper from phenobarbital is preferred. In a comparison study, a rapid taper using benzodiazepines was found to be superior to a phenobarbital rapid taper.
• Pregabalin may help reduce the severity of benzodiazepine withdrawal symptoms, and reduce the risk of relapse.
• Propranolol was not found to increase the discontinuation success rate.
• SSRI antidepressants have been found to have little value in the treatment of benzodiazepine withdrawal.
• Trazodone was not found to increase the discontinuation success rate.

Inpatient treatment

Inpatient drug detox or rehabilitation facilities may be inappropriate for those who have become tolerant or dependent while taking the drug as prescribed, as opposed to recreational use. Such inpatient referrals may be traumatic for non-abusers.

Prognosis

A 2006 meta-analysis found evidence for the efficacy of stepped care: minimal intervention (e.g. send an advisory letter, or meet large number of patients to advise discontinuation), followed by systematic tapered discontinuation alone without augmentation if the first try was unsuccessful. Cognitive behavioral therapy improved discontinuation success rates for panic disorder, melatonin for insomnia, and flumazenil or sodium valproate for general long-term benzodiazepine use. A ten-year follow-up found that more than half of those who had successfully withdrawn from long-term use were still abstinent two years later, and that if they were able to maintain this state at two years, they were likely to maintain this state at the ten-year followup. One study found that after one year of abstinence from long-term use of benzodiazepines, cognitive, neurological and intellectual impairments had returned to normal.

Those who had a prior psychiatric diagnosis had a similar success rate from a gradual taper at a two-year follow-up. Withdrawal from benzodiazepines did not lead to an increased use of antidepressants.

Withdrawal process

It can be too difficult to withdraw from short- or intermediate-acting benzodiazepines because of the intensity of the rebound symptoms felt between doses. Moreover, short-acting benzodiazepines appear to produce a more intense withdrawal syndrome. For this reason, discontinuation is sometimes carried out by first substituting an equivalent dose of a short-acting benzodiazepine with a longer-acting one like diazepam or chlordiazepoxide. Failure to use the correct equivalent amount can precipitate a severe withdrawal reaction. Benzodiazepines with a half-life of more than 24 hours include chlordiazepoxide, diazepam, clobazam, clonazepam, chlorazepinic acid, ketazolam, medazepam, nordazepam, and prazepam. Benzodiazepines with a half-life of less than 24 hours include alprazolam, bromazepam, brotizolam, flunitrazepam, loprazolam, lorazepam, lormetazepam, midazolam, nitrazepam, oxazepam, and temazepam. The resultant equivalent dose is then gradually reduced.

The consensus is to reduce dosage gradually over several weeks, e.g. 4 or more weeks for diazepam doses over 30 mg/day, with the rate determined by the person's ability to tolerate symptoms. The recommended reduction rates range from 50% of the initial dose every week or so, to 10-25% of the daily dose every 2 weeks. For example, the reduction rate used in the Heather Ashton protocol calls for eliminating 10% of the remaining dose every two to four weeks, depending on the severity and response to reductions with the final dose at 0.5 mg dose of diazepam or 2.5 mg dose of chlordiazepoxide. For most people, discontinuation over 4-6 weeks or 4-8 weeks is suitable. Prolonged period of reduction over many months should be avoided to prevent the withdrawal process from becoming a "morbid focus" for the person.

Duration

After the last dose has been taken, the acute phase of the withdrawal generally lasts for about two months although withdrawal symptoms, even from low-dose use, can persist for six to twelve months gradually improving over that period, however, clinically significant withdrawal symptoms may persist for years, although gradually declining.

A clinical trial of patients taking the benzodiazepine alprazolam for as short as eight weeks triggered protracted symptoms of memory deficits which were still present up to eight weeks after cessation of alprazolam.

Protracted withdrawal syndrome

Protracted withdrawal syndrome refers to symptoms persisting for months or even years. A significant minority of people withdrawing from benzodiazepines, perhaps 10% to 15%, experience a protracted withdrawal syndrome which can sometimes be severe. Symptoms may include tinnitus, psychosis, cognitive deficits, gastrointestinal complaints, insomnia, paraesthesia (tingling and numbness), pain (usually in limbs and extremities), muscle pain, weakness, tension, painful tremor, shaking attacks, jerks, dizziness and blepharospasm and may occur even without a pre-existing history of these symptoms. Tinnitus occurring during dose reduction or discontinuation of benzodiazepines is alleviated by recommencement of benzodiazepines. Dizziness is often reported as being the withdrawal symptom that lasts the longest.

A study testing neuropsychological factors found psychophysiological markers differing from normals, and concluded that protracted withdrawal syndrome was a genuine iatrogenic condition caused by the long-term use. The causes of persisting symptoms are a combination of pharmacological factors such as persisting drug induced receptor changes, psychological factors both caused by the drug and separate from the drug and possibly in some cases, particularly high dose users, structural brain damage or structural neuronal damage. Symptoms continue to improve over time, often to the point where people eventually resume their normal lives, even after years of incapacity.

A slow withdrawal rate significantly reduces the risk of a protracted or severe withdrawal state. Protracted withdrawal symptoms can be punctuated by periods of good days and bad days. When symptoms increase periodically during protracted withdrawal, physiological changes may be present, including dilated pupils as well as an increase in blood pressure and heart rate. The change in symptoms has been proposed to be due to changes in receptor sensitivity for GABA during the process of tolerance reversal.^[6] A meta-analysis found cognitive impairments in many areas due to benzodiazepine use show improvements after six months of withdrawal, but significant impairments in most areas may be permanent or may require more than six months to reverse.

Protracted symptoms continue to fade over a period of many months or several years. There is no known cure for protracted benzodiazepine withdrawal syndrome except time, however, the medication flumazenil was found to be more effective than placebo in reducing feelings of hostility and aggression in patients who had been free of benzodiazepines for 4–266 weeks. This may suggest a role for flumazenil in treating protracted benzodiazepine withdrawal symptoms.

Epidemiology

The severity and length of the withdrawal syndrome is likely determined by various factors, including rate of tapering, length of use and dosage size, and possible genetic factors. Those who have a prior history of withdrawing from benzodiazepines may have a sensitized or kindled central nervous system leading to worsening cognition and symptomatology, and making each subsequent withdrawal period worse.

Special populations

Pediatrics

A neonatal withdrawal syndrome, sometimes severe, can occur when the mother had taken benzodiazepines, especially during the third trimester. Symptoms include hypotonia, apnoeic spells, cyanosis, impaired metabolic responses to cold stress, and seizures. The neonatal benzodiazepine withdrawal syndrome has been reported to persist from hours to months after birth.

A withdrawal syndrome is seen in about 20% of pediatric intensive care unit children after infusions with benzodiazepines or opioids. The likelihood of having the syndrome correlates with total infusion duration and dose, although duration is thought to be more important. Treatment for withdrawal usually involves weaning over a 3- to 21-day period if the infusion lasted for more than a week. Symptoms include tremors, agitation, sleeplessness, inconsolable crying, diarrhea and sweating. In total, over fifty withdrawal symptoms are listed in this review article. Environmental measures aimed at easing the symptoms of neonates with severe abstinence syndrome had little impact, but providing a quiet sleep environment helped in mild cases.

Pregnancy

Discontinuing benzodiazepines or antidepressants abruptly due to concerns of teratogenic effects of the medications has a high risk of causing serious complications, so is not recommended. For example, abrupt withdrawal of benzodiazepines or antidepressants has a high risk of causing extreme withdrawal symptoms, including suicidal ideation and a severe rebound effect of the return of the underlying disorder if present. This can lead to hospitalisation and potentially, suicide. One study reported one-third of mothers who suddenly discontinued or very rapidly tapered their medications became acutely suicidal due to 'unbearable symptoms'. One woman had a medical abortion, as she felt she could no longer cope, and another woman used alcohol in a bid to combat the withdrawal symptoms from benzodiazepines. Spontaneous abortions may also result from abrupt withdrawal of psychotropic medications, including benzodiazepines. The study reported physicians generally are not aware of the severe consequences of abrupt withdrawal of psychotropic medications such as benzodiazepines or antidepressants.

Elderly

A study of the elderly who were benzodiazepine dependent found withdrawal could be carried out with few complications and could lead to improvements in sleep and cognitive abilities. At 52 weeks after successful withdrawal, a 22% improvement in cognitive status was found, as well as improved social functioning. Those who remained on benzodiazepines experienced a 5% decline in cognitive abilities, which seemed to be faster than that seen in normal aging, suggesting the longer the intake of benzodiazepines, the worse the cognitive effects become. Some worsening of symptoms were seen in the first few months of benzodiazepine abstinence, but at a 24-week followup, elderly subjects were clearly improved compared to those who remained on benzodiazepines. Improvements in sleep were seen at the 24- and 52-week followups. The authors concluded benzodiazepines were not effective in the long term for sleep problems except in suppressing withdrawal-related rebound insomnia. Improvements were seen between 24 and 52 weeks after withdrawal in many factors, including improved sleep and several cognitive and performance abilities. Some cognitive abilities, which are sensitive to benzodiazepines, as well as age, such as episodic memory did not improve. The authors, however, cited a study in younger patients who at a 3.5-year followup showed no memory impairments and speculated that certain memory functions take longer to recover from chronic benzodiazepine use and further improvements in elderly people's cognitive function may occur beyond 52 weeks after withdrawal. The reason it took 24 weeks for improvements to be seen after cessation of benzodiazepine use was due to the time it takes the brain to adapt to the benzodiazepine-free environment.

At 24 weeks, significant improvements were found, including accuracy of information processing improved, but a decline was seen in those who remained on benzodiazepines. Further improvements were noted at the 52-week followup, indicating ongoing improvements with benzodiazepine abstinence. Younger people on benzodiazepines also experience cognitive deterioration in visual spatial memory, but are not as vulnerable as the elderly to the cognitive effects. Improved reaction times were noted at 52 weeks in elderly patients free from benzodiazepines. This is an important function in the elderly, especially if they drive a car due to the increased risk of road traffic accidents in benzodiazepine users. At the 24-week followup, 80% of people had successfully withdrawn from benzodiazepines. Part of the success was attributed to the placebo method used for part of the trial which broke the psychological dependence on benzodiazepines when the elderly patients realised they had completed their gradual reduction several weeks previously, and had only been taking placebo tablets. This helped reassure them they could sleep without their pills.

The authors also warned of the similarities in pharmacology and mechanism of action of the newer nonbenzodiazepine Z drugs.

The elimination half-life of diazepam and chlordiazepoxide, as well as other long half-life benzodiazepines, is twice as long in the elderly compared to younger individuals. Many doctors do not adjust benzodiazepine dosage according to age in elderly patients.

Barbiturate

From Wikipedia, the free encyclopedia

Barbituric acid, the parent structure of all barbiturates

A barbiturate is a drug that acts as a central nervous system depressant. Barbiturates are effective as anxiolytics, hypnotics, and anticonvulsants, but have physical and psychological addiction potential as well as overdose potential among other possible adverse effects. They have largely been replaced by benzodiazepines and nonbenzodiazepines ("Z-drugs") in routine medical practice, particularly in the treatment of anxiety and insomnia, due to the significantly lower risk of addiction and overdose and the lack of an antidote for barbiturate overdose. Despite this, barbiturates are still in use for various purposes: in general anesthesia, epilepsy, treatment of acute migraines or cluster headaches, acute tension headaches, euthanasia, capital punishment, and assisted suicide.

The name barbiturate originates from the fact that they are all chemical derivatives of barbituric acid.

Uses

Medicine

Barbiturates such as phenobarbital were long used as anxiolytics and hypnotics. Intermediate-acting barbiturates reduce time to fall asleep, increase total sleep time, and reduce REM sleep time. Today they have been largely replaced by benzodiazepines for these purposes because the latter are less toxic in drug overdose. However, barbiturates are still used as anticonvulsants (e.g., phenobarbital and primidone) and general anesthetics (e.g., sodium thiopental).

Barbiturates in high doses are used for physician-assisted suicide, and in combination with a muscle relaxant for euthanasia and for capital punishment by lethal injection. Barbiturates are frequently employed as euthanizing agents in small-animal veterinary medicine.

Interrogation

Sodium thiopental is an ultra-short-acting barbiturate that is marketed under the name Sodium Pentothal. It is often mistaken for "truth serum", or sodium amytal, an intermediate-acting barbiturate that is used for sedation and to treat insomnia, but was also used in so-called sodium amytal "interviews" where the person being questioned would be much more likely to provide the truth whilst under the influence of this drug. When dissolved in water, sodium amytal can be swallowed, or it can be administered by intravenous injection. The drug does not itself force people to tell the truth, but is thought to decrease inhibitions and slow creative thinking, making subjects more likely to be caught off guard when questioned, and increasing the possibility of the subject revealing information through emotional outbursts. Lying is somewhat more complex than telling the truth, especially under the influence of a sedative-hypnotic drug.

The memory-impairing effects and cognitive impairments induced by sodium thiopental are thought to reduce a subject's ability to invent and remember lies. This practice is no longer considered legally admissible in court due to findings that subjects undergoing such interrogations may form false memories, putting the reliability of all information obtained through such methods into question. Nonetheless, it is still employed in certain circumstances by defense and law enforcement agencies as a "humane" alternative to torture interrogation when the subject is believed to have information critical to the security of the state or agency employing the tactic.

Chemistry

In 1988, the synthesis and binding studies of an artificial receptor binding barbiturates by six complementary hydrogen bonds was published. Since this first article, different kind of receptors were designed, as well as different barbiturates and cyanurates, not for their efficiencies as drugs but for applications in supramolecular chemistry, in the conception of materials and molecular devices.

Sodium barbital and barbital have also been used as pH buffers for biological research, e.g., in immuno-electrophoresis or in fixative solutions.

Side effects

Addiction experts in psychiatry, chemistry, pharmacology, forensic science, epidemiology, and the police and legal services engaged in delphic analysis regarding 20 popular recreational drugs. Barbiturates were ranked last in dependence, 3rd in physical harm, and 4th in social harm.

There are special risks to consider for older adults, and women who are pregnant. When a person ages, the body becomes less able to rid itself of barbiturates. As a result, people over the age of sixty-five are at higher risk of experiencing the harmful effects of barbiturates, including drug dependence and accidental overdose. When barbiturates are taken during pregnancy, the drug passes through the placenta to the fetus. After the baby is born, it may experience withdrawal symptoms and have trouble breathing. In addition, nursing mothers who take barbiturates may transmit the drug to their babies through breast milk. A rare adverse reaction to barbiturates is Stevens–Johnson syndrome, which primarily affects the mucous membranes.

Tolerance and dependence

With regular use, tolerance to the effects of barbiturates develops. Research shows tolerance can develop with even one administration of a barbiturate. As with all GABAergic drugs, barbiturate withdrawal produces potentially fatal effects such as seizures, in a manner reminiscent of delirium tremens and benzodiazepine withdrawal although its more direct mechanism of GABA agonism makes barbiturate withdrawal even more severe than that of alcohol or benzodiazepines (subsequently making it one of the most dangerous withdrawals of any known addictive substance). Similarly to benzodiazepines, the longer acting barbiturates produce a less severe withdrawal syndrome than short acting and ultra-short acting barbiturates. Withdrawal symptoms are dose-dependent with heavier users being more affected than lower-dose addicts.

The pharmacological treatment of barbiturate withdrawal is an extended process often consisting of converting the patient to a long-acting benzodiazepine (i.e. Valium), followed by slowly tapering off the benzodiazepine. Mental cravings for barbiturates can last for months or years in some cases and counselling/support groups are highly encouraged by addiction specialists. Patients should never try to tackle the task of discontinuing barbiturates without consulting a doctor, due to the high lethality and relatively sudden onset of the withdrawal. Attempting to quit "cold turkey" may result in serious neurological damage, severe physical injuries received during convulsions, and even death via glutamatergic excitotoxicity.

Overdose

Some symptoms of an overdose typically include sluggishness, incoordination, difficulty in thinking, slowness of speech, faulty judgement, drowsiness, shallow breathing, staggering, and, in severe cases, coma or death. The lethal dosage of barbiturates varies greatly with tolerance and from one individual to another. The lethal dose is highly variable among different members of the class, with superpotent barbiturates such as pentobarbital being potentially fatal in considerably lower doses than the low-potency barbiturates such as butalbital. Even in inpatient settings, the development of tolerance is still a problem, as dangerous and unpleasant withdrawal symptoms can result when the drug is stopped after dependence has developed. Tolerance to the anxiolytic and sedative effects of barbiturates tends to develop faster than tolerance to their effects on smooth muscle, respiration, and heart rate, making them generally unsuitable for a long time psychiatric use. Tolerance to the anticonvulsant effects tends to correlate more with tolerance to physiological effects, however, meaning that they are still a viable option for long-term epilepsy treatment.

Barbiturates in overdose with other CNS (central nervous system) depressants (e.g. alcohol, opiates, benzodiazepines) are even more dangerous due to additive CNS and respiratory depressant effects. In the case of benzodiazepines, not only do they have additive effects, barbiturates also increase the binding affinity of the benzodiazepine binding site, leading to exaggerated benzodiazepine effects. (ex. If a benzodiazepine increases the frequency of channel opening by 300%, and a barbiturate increases the duration of their opening by 300%, then the combined effects of the drugs increase the channels overall function by 900%, not 600%).

The longest-acting barbiturates have half-lives of a day or more, and subsequently result in bioaccumulation of the drug in the system. The therapeutic and recreational effects of long-acting barbiturates wear off significantly faster than the drug can be eliminated, allowing the drug to reach toxic concentrations in the blood following repeated administration (even when taken at the therapeutic or prescribed dose) despite the user feeling little or no effects from the plasma-bound concentrations of the drug. Users who consume alcohol or other sedatives after the drug's effects have worn off, but before it has cleared the system, may experience a greatly exaggerated effect from the other sedatives which can be incapacitating or even fatal.

Barbiturates induce a number of hepatic CYP enzymes (most notably CYP2C9, CYP2C19, and CYP3A4), leading to exaggerated effects from many prodrugs and decreased effects from drugs which are metabolized by these enzymes to inactive metabolites. This can result in fatal overdoses from drugs such as codeine, tramadol, and carisoprodol, which become considerably more potent after being metabolized by CYP enzymes. Although all known members of the class possess relevant enzyme induction capabilities, the degree of induction overall as well as the impact on each specific enzyme span a broad range, with phenobarbital and secobarbital being the most potent enzyme inducers and butalbital and talbutal being among the weakest enzyme inducers in the class.

People who are known to have committed suicide by barbiturate overdose include Charles Boyer, Ruan Lingyu, Dalida, Jeannine "The Singing Nun" Deckers, Felix Hausdorff, Abbie Hoffman, Phyllis Hyman, C. P. Ramanujam, George Sanders, Jean Seberg, Lupe Vélez and the members of Heaven's Gate cult. Others who have died as a result of barbiturate overdose include Pier Angeli, Brian Epstein, Judy Garland, Jimi Hendrix, Marilyn Monroe, Inger Stevens, Dinah Washington, Ellen Wilkinson, and Alan Wilson; in some cases these have been speculated to be suicides as well. Those who died of a combination of barbiturates and other drugs include Rainer Werner Fassbinder, Dorothy Kilgallen, Malcolm Lowry, Edie Sedgwick and Kenneth Williams. Dorothy Dandridge died of either an overdose or an unrelated embolism. Ingeborg Bachmann may have died of the consequences of barbiturate withdrawal (she was hospitalized with burns, the doctors treating her not being aware of her barbiturate addiction).

Mechanism of action

Barbiturates act as positive allosteric modulators and, at higher doses, as agonists of GABA_A receptors. GABA is the principal inhibitory neurotransmitter in the mammalian central nervous system (CNS). Barbiturates bind to the GABA_A receptor at multiple homologous transmembrane pockets located at subunit interfaces, which are binding sites distinct from GABA itself and also distinct from the benzodiazepine binding site. Like benzodiazepines, barbiturates potentiate the effect of GABA at this receptor. In addition to this GABAergic effect, barbiturates also block AMPA and kainate receptors, subtypes of ionotropic glutamate receptor. Glutamate is the principal excitatory neurotransmitter in the mammalian CNS. Taken together, the findings that barbiturates potentiate inhibitory GABA_A receptors and inhibit excitatory AMPA receptors can explain the superior CNS-depressant effects of these agents to alternative GABA potentiating agents such as benzodiazepines and quinazolinones. At higher concentration, they inhibit the Ca²⁺-dependent release of neurotransmitters such as glutamate via an effect on P/Q-type voltage-dependent calcium channels. Barbiturates produce their pharmacological effects by increasing the duration of chloride ion channel opening at the GABA_A receptor (pharmacodynamics: This increases the efficacy of GABA), whereas benzodiazepines increase the frequency of the chloride ion channel opening at the GABA_A receptor (pharmacodynamics: This increases the potency of GABA). The direct gating or opening of the chloride ion channel is the reason for the increased toxicity of barbiturates compared to benzodiazepines in overdose.

Further, barbiturates are relatively non-selective compounds that bind to an entire superfamily of ligand-gated ion channels, of which the GABA_A receptor channel is only one of several representatives. This Cys-loop receptor superfamily of ion channels includes the neuronal nACh receptor channel, the 5-HT₃ receptor channel, and the glycine receptor channel. However, while GABA_A receptor currents are increased by barbiturates (and other general anesthetics), ligand-gated ion channels that are predominantly permeable for cationic ions are blocked by these compounds. For example, neuronal nAChR channels are blocked by clinically relevant anesthetic concentrations of both thiopental and pentobarbital. Such findings implicate (non-GABA-ergic) ligand-gated ion channels, e.g. the neuronal nAChR channel, in mediating some of the (side) effects of barbiturates. This is the mechanism responsible for the (mild to moderate) anesthetic effect of barbiturates in high doses when used in anesthetic concentration.

History

Barbituric acid was first synthesized November 27, 1864, by German chemist Adolf von Baeyer. This was done by condensing urea with diethyl malonate. There are several stories about how the substance got its name. The most likely story is that Baeyer and his colleagues went to celebrate their discovery in a tavern where the town's artillery garrison were also celebrating the feast of Saint Barbara – the patron saint of artillerymen. An artillery officer is said to have christened the new substance by amalgamating Barbara with urea. Another story was barbiturate was invented on the feast day of St. Barbara. Another story holds that Baeyer synthesized the substance from the collected urine of a Munich waitress named Barbara. No substance of medical value was discovered, however, until 1903 when two German scientists working at Bayer, Emil Fischer and Joseph von Mering, discovered that barbital was very effective in putting dogs to sleep. Barbital was then marketed by Bayer under the trade name Veronal. It is said that Mering proposed this name because the most peaceful place he knew was the Italian city of Verona.

It was not until the 1950s that the behavioral disturbances and physical dependence potential of barbiturates became recognized.

Barbituric acid itself does not have any direct effect on the central nervous system and chemists have derived over 2,500 compounds from it that possess pharmacologically active qualities. The broad class of barbiturates is further broken down and classified according to speed of onset and duration of action. Ultrashort-acting barbiturates are commonly used for anesthesia because their extremely short duration of action allows for greater control. These properties allow doctors to rapidly put a patient "under" in emergency surgery situations. Doctors can also bring a patient out of anesthesia just as quickly, should complications arise during surgery. The middle two classes of barbiturates are often combined under the title "short/intermediate-acting." These barbiturates are also employed for anesthetic purposes, and are also sometimes prescribed for anxiety or insomnia. This is not a common practice anymore, however, owing to the dangers of long-term use of barbiturates; they have been replaced by the benzodiazepines and Z-drugs such as zolpidem, zaleplon and eszopiclone for sleep. The final class of barbiturates are known as long-acting barbiturates (the most notable one being phenobarbital, which has a half-life of roughly 92 hours). This class of barbiturates is used almost exclusively as anticonvulsants, although on rare occasions they are prescribed for daytime sedation. Barbiturates in this class are not used for insomnia, because, owing to their extremely long half-life, patients would awake with a residual "hang-over" effect and feel groggy.

Barbiturates can in most cases be used either as the free acid or as salts of sodium, calcium, potassium, magnesium, lithium, etc. Codeine- and Dionine-based salts of barbituric acid have been developed. In 1912, Bayer introduced another barbituric acid derivative, phenobarbital, under the trade name Luminal, as a sedative–hypnotic.

Society and culture

Legal status

During World War II, military personnel in the Pacific region were given "goofballs" to allow them to tolerate the heat and humidity of daily working conditions. Goofballs were distributed to reduce the demand on the respiratory system, as well as maintaining blood pressure, to combat the extreme conditions. Many soldiers returned with addictions that required several months of rehabilitation before discharge. This led to growing dependency problems, often exacerbated by indifferent doctors prescribing high doses to unknowing patients through the 1950s and 1960s.

In the late 1950s and 1960s, an increasing number of published reports of barbiturate overdoses and dependence problems led physicians to reduce their prescription, particularly for spurious requests. This eventually led to the scheduling of barbiturates as controlled drugs.

In the Netherlands, the Opium Law classifies all barbiturates as List II drugs, with the exception of secobarbital, which is on List I.

There is a small group of List II drugs for which doctors have to write the prescriptions according to the same, tougher guidelines as those for List I drugs (writing the prescription in full in letters, listing the patients name, and have to contain the name and initials, address, city and telephone number of the licensed prescriber issuing the prescriptions, as well as the name and initials, address and city of the person the prescription is issued to). Among that group of drugs are the barbiturates amobarbital, butalbital, cyclobarbital, and pentobarbital.

In the United States, the Controlled Substances Act of 1970 classified most barbiturates as controlled substances—and they remain so as of September 2020. Barbital, methylphenobarbital (also known as mephobarbital), and phenobarbital are designated schedule IV drugs, and "Any substance which contains any quantity of a derivative of barbituric acid, or any salt of a derivative of barbituric acid" (all other barbiturates) were designated as being schedule III. Under the original CSA, no barbiturates were placed in schedule I, II, or V; however, amobarbital, pentobarbital, and secobarbital are schedule II controlled substances unless they are in a suppository dosage form.

In 1971, the Convention on Psychotropic Substances was signed in Vienna. Designed to regulate amphetamines, barbiturates, and other synthetics, the 34th version of the treaty, as of 25 January 2014, regulates secobarbital as schedule II, amobarbital, butalbital, cyclobarbital, and pentobarbital as schedule III, and allobarbital, barbital, butobarbital, mephobarbital, phenobarbital, butabarbital, and vinylbital as schedule IV on its "Green List". The combination medication Fioricet, consisting of butalbital, caffeine, and paracetamol (acetaminophen), however, is specifically exempted from controlled substance status, while its sibling Fiorinal, which contains aspirin instead of paracetamol and may contain codeine phosphate, remains a schedule III drug.

Recreational use

Recreational users report that a barbiturate high gives them feelings of relaxed contentment and euphoria. Physical and psychological dependence may also develop with repeated use. Chronic misuse of barbiturates is associated with significant morbidity. One study found that 11% of males and 23% of females with a sedative-hypnotic misuse die by suicide. Other effects of barbiturate intoxication include drowsiness, lateral and vertical nystagmus, slurred speech and ataxia, decreased anxiety, and loss of inhibitions. Barbiturates are also used to alleviate the adverse or withdrawal effects of illicit drug use, in a manner similar to long-acting benzodiazepines such as diazepam and clonazepam. Often poly drug abuse occurs: Barbiturates are consumed with or substituted by other available substances, most commonly alcohol.

Drug users tend to prefer short-acting and intermediate-acting barbiturates. The most commonly used are amobarbital (Amytal), pentobarbital (Nembutal), and secobarbital (Seconal). A combination of amobarbital and secobarbital (called Tuinal) is also highly used. Short-acting and intermediate-acting barbiturates are usually prescribed as sedatives and sleeping pills. These pills begin acting fifteen to forty minutes after they are swallowed, and their effects last from five to six hours.

Slang terms for barbiturates include barbs, barbies, bluebirds, dolls, wallbangers, yellows, downers, goofballs, sleepers, 'reds & blues', and tooties.

Examples

Generic structure of a barbiturate, including numbering scheme

Barbiturates

Short Name	R1	R2	IUPAC Name
allobarbital	CH2CHCH2	CH2CHCH2	5,5-diallylbarbiturate
amobarbital	CH2CH3	(CH2)2CH(CH3)2	5-ethyl-5-isopentyl-barbiturate
aprobarbital	CH2CHCH2	CH(CH3)2	5-allyl-5-isopropyl-barbiturate
alphenal	CH2CHCH2	C6H5	5-allyl-5-phenyl-barbiturate
barbital	CH2CH3	CH2CH3	5,5-diethylbarbiturate
brallobarbital	CH2CHCH2	CH2CBrCH2	5-allyl-5-(2-bromo-allyl)-barbiturate
pentobarbital	CH2CH3	CHCH3(CH2)2CH3	5-ethyl-5-(1-methylbutyl)-barbiturate
phenobarbital	CH2CH3	C6H5	5-ethyl-5-phenylbarbiturate
Primidone
secobarbital	CH2CHCH2	CHCH3(CH2)2CH3	5-[(2R)-pentan-2-yl]-5-prop-2-enyl-barbiturate; 5-allyl-5-[(2R)-pentan-2-yl]-barbiturate

Thiopental is a barbiturate with one of the C-O double bonds (with the carbon being labelled 2 in the adjacent diagram) replaced with a C-S double bond, R¹ being CH₂CH₃ and R² being CH(CH₃)CH₂CH₂CH₃.

Celestial spheres

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Celestial_spheres 

Geocentric celestial spheres; Peter Apian's Cosmographia (Antwerp, 1539)

The celestial spheres, or celestial orbs, were the fundamental entities of the cosmological models developed by Plato, Eudoxus, Aristotle, Ptolemy, Copernicus, and others. In these celestial models, the apparent motions of the fixed stars and planets are accounted for by treating them as embedded in rotating spheres made of an aetherial, transparent fifth element (quintessence), like jewels set in orbs. Since it was believed that the fixed stars did not change their positions relative to one another, it was argued that they must be on the surface of a single starry sphere.

In modern thought, the orbits of the planets are viewed as the paths of those planets through mostly empty space. Ancient and medieval thinkers, however, considered the celestial orbs to be thick spheres of rarefied matter nested one within the other, each one in complete contact with the sphere above it and the sphere below. When scholars applied Ptolemy's epicycles, they presumed that each planetary sphere was exactly thick enough to accommodate them. By combining this nested sphere model with astronomical observations, scholars calculated what became generally accepted values at the time for the distances to the Sun: about 4 million miles (6.4 million kilometres), to the other planets, and to the edge of the universe: about 73 million miles (117 million kilometres). The nested sphere model's distances to the Sun and planets differ significantly from modern measurements of the distances, and the size of the universe is now known to be inconceivably large and continuously expanding.

Albert Van Helden has suggested that from about 1250 until the 17th century, virtually all educated Europeans were familiar with the Ptolemaic model of "nesting spheres and the cosmic dimensions derived from it". Even following the adoption of Copernicus's heliocentric model of the universe, new versions of the celestial sphere model were introduced, with the planetary spheres following this sequence from the central Sun: Mercury, Venus, Earth-Moon, Mars, Jupiter and Saturn.

Mainstream belief in the theory of celestial spheres did not survive the Scientific Revolution. In the early 1600s, Kepler continued to discuss celestial spheres, although he did not consider that the planets were carried by the spheres but held that they moved in elliptical paths described by Kepler's laws of planetary motion. In the late 1600s, Greek and medieval theories concerning the motion of terrestrial and celestial objects were replaced by Newton's law of universal gravitation and Newtonian mechanics, which explain how Kepler's laws arise from the gravitational attraction between bodies.

History

Early ideas of spheres and circles

In Greek antiquity the ideas of celestial spheres and rings first appeared in the cosmology of Anaximander in the early 6th century BC. In his cosmology both the Sun and Moon are circular open vents in tubular rings of fire enclosed in tubes of condensed air; these rings constitute the rims of rotating chariot-like wheels pivoting on the Earth at their centre. The fixed stars are also open vents in such wheel rims, but there are so many such wheels for the stars that their contiguous rims all together form a continuous spherical shell encompassing the Earth. All these wheel rims had originally been formed out of an original sphere of fire wholly encompassing the Earth, which had disintegrated into many individual rings. Hence, in Anaximanders's cosmogony, in the beginning was the sphere, out of which celestial rings were formed, from some of which the stellar sphere was in turn composed. As viewed from the Earth, the ring of the Sun was highest, that of the Moon was lower, and the sphere of the stars was lowest.

Following Anaximander, his pupil Anaximenes (c. 585–528/4) held that the stars, Sun, Moon, and planets are all made of fire. But whilst the stars are fastened on a revolving crystal sphere like nails or studs, the Sun, Moon, and planets, and also the Earth, all just ride on air like leaves because of their breadth. And whilst the fixed stars are carried around in a complete circle by the stellar sphere, the Sun, Moon and planets do not revolve under the Earth between setting and rising again like the stars do, but rather on setting they go laterally around the Earth like a cap turning halfway around the head until they rise again. And unlike Anaximander, he relegated the fixed stars to the region most distant from the Earth. The most enduring feature of Anaximenes' cosmos was its conception of the stars being fixed on a crystal sphere as in a rigid frame, which became a fundamental principle of cosmology down to Copernicus and Kepler.

After Anaximenes, Pythagoras, Xenophanes and Parmenides all held that the universe was spherical. And much later in the fourth century BC Plato's Timaeus proposed that the body of the cosmos was made in the most perfect and uniform shape, that of a sphere containing the fixed stars. But it posited that the planets were spherical bodies set in rotating bands or rings rather than wheel rims as in Anaximander's cosmology.

Emergence of the planetary spheres

Instead of bands, Plato's student Eudoxus developed a planetary model using concentric spheres for all the planets, with three spheres each for his models of the Moon and the Sun and four each for the models of the other five planets, thus making 26 spheres in all. Callippus modified this system, using five spheres for his models of the Sun, Moon, Mercury, Venus, and Mars and retaining four spheres for the models of Jupiter and Saturn, thus making 33 spheres in all. Each planet is attached to the innermost of its own particular set of spheres. Although the models of Eudoxus and Callippus qualitatively describe the major features of the motion of the planets, they fail to account exactly for these motions and therefore cannot provide quantitative predictions. Although historians of Greek science have traditionally considered these models to be merely geometrical representations, recent studies have proposed that they were also intended to be physically real or have withheld judgment, noting the limited evidence to resolve the question.

In his Metaphysics, Aristotle developed a physical cosmology of spheres, based on the mathematical models of Eudoxus. In Aristotle's fully developed celestial model, the spherical Earth is at the centre of the universe and the planets are moved by either 47 or 55 interconnected spheres that form a unified planetary system, whereas in the models of Eudoxus and Callippus each planet's individual set of spheres were not connected to those of the next planet. Aristotle says the exact number of spheres, and hence the number of movers, is to be determined by astronomical investigation, but he added additional spheres to those proposed by Eudoxus and Callippus, to counteract the motion of the outer spheres. Aristotle considers that these spheres are made of an unchanging fifth element, the aether. Each of these concentric spheres is moved by its own god—an unchanging divine unmoved mover, and who moves its sphere simply by virtue of being loved by it.

Ptolemaic model of the spheres for Venus, Mars, Jupiter, and Saturn with epicycle, eccentric deferent and equant point. Georg von Peuerbach, Theoricae novae planetarum, 1474.

In his Almagest, the astronomer Ptolemy (fl. ca. 150 AD) developed geometrical predictive models of the motions of the stars and planets and extended them to a unified physical model of the cosmos in his Planetary hypotheses. By using eccentrics and epicycles, his geometrical model achieved greater mathematical detail and predictive accuracy than had been exhibited by earlier concentric spherical models of the cosmos. In Ptolemy's physical model, each planet is contained in two or more spheres, but in Book 2 of his Planetary Hypotheses Ptolemy depicted thick circular slices rather than spheres as in its Book 1. One sphere/slice is the deferent, with a centre offset somewhat from the Earth; the other sphere/slice is an epicycle embedded in the deferent, with the planet embedded in the epicyclical sphere/slice. Ptolemy's model of nesting spheres provided the general dimensions of the cosmos, the greatest distance of Saturn being 19,865 times the radius of the Earth and the distance of the fixed stars being at least 20,000 Earth radii.

The planetary spheres were arranged outwards from the spherical, stationary Earth at the centre of the universe in this order: the spheres of the Moon, Mercury, Venus, Sun, Mars, Jupiter, and Saturn. In more detailed models the seven planetary spheres contained other secondary spheres within them. The planetary spheres were followed by the stellar sphere containing the fixed stars; other scholars added a ninth sphere to account for the precession of the equinoxes, a tenth to account for the supposed trepidation of the equinoxes, and even an eleventh to account for the changing obliquity of the ecliptic. In antiquity the order of the lower planets was not universally agreed. Plato and his followers ordered them Moon, Sun, Mercury, Venus, and then followed the standard model for the upper spheres. Others disagreed about the relative place of the spheres of Mercury and Venus: Ptolemy placed both of them beneath the Sun with Venus above Mercury, but noted others placed them both above the Sun; some medieval thinkers, such as al-Bitruji, placed the sphere of Venus above the Sun and that of Mercury below it.

Middle Ages

Astronomical discussions

The Earth within seven celestial spheres, from Bede, De natura rerum, late 11th century

A series of astronomers, beginning with the Muslim astronomer al-Farghānī, used the Ptolemaic model of nesting spheres to compute distances to the stars and planetary spheres. Al-Farghānī's distance to the stars was 20,110 Earth radii which, on the assumption that the radius of the Earth was 3,250 miles (5,230 kilometres), came to 65,357,500 miles (105,182,700 kilometres). An introduction to Ptolemy's Almagest, the Tashil al-Majisti, believed to be written by Thābit ibn Qurra, presented minor variations of Ptolemy's distances to the celestial spheres. In his Zij, Al-Battānī presented independent calculations of the distances to the planets on the model of nesting spheres, which he thought was due to scholars writing after Ptolemy. His calculations yielded a distance of 19,000 Earth radii to the stars.

Around the turn of the millennium, the Arabic astronomer and polymath Ibn al-Haytham (Alhacen) presented a development of Ptolemy's geocentric models in terms of nested spheres. Despite the similarity of this concept to that of Ptolemy's Planetary Hypotheses, al-Haytham's presentation differs in sufficient detail that it has been argued that it reflects an independent development of the concept. In chapters 15–16 of his Book of Optics, Ibn al-Haytham also said that the celestial spheres do not consist of solid matter.

Near the end of the twelfth century, the Spanish Muslim astronomer al-Bitrūjī (Alpetragius) sought to explain the complex motions of the planets without Ptolemy's epicycles and eccentrics, using an Aristotelian framework of purely concentric spheres that moved with differing speeds from east to west. This model was much less accurate as a predictive astronomical model, but it was discussed by later European astronomers and philosophers.

In the thirteenth century the astronomer al-'Urḍi proposed a radical change to Ptolemy's system of nesting spheres. In his Kitāb al-Hayáh, he recalculated the distance of the planets using parameters which he redetermined. Taking the distance of the Sun as 1,266 Earth radii, he was forced to place the sphere of Venus above the sphere of the Sun; as a further refinement, he added the planet's diameters to the thickness of their spheres. As a consequence, his version of the nesting spheres model had the sphere of the stars at a distance of 140,177 Earth radii.

About the same time, scholars in European universities began to address the implications of the rediscovered philosophy of Aristotle and astronomy of Ptolemy. Both astronomical scholars and popular writers considered the implications of the nested sphere model for the dimensions of the universe. Campanus of Novara's introductory astronomical text, the Theorica planetarum, used the model of nesting spheres to compute the distances of the various planets from the Earth, which he gave as 22,612 Earth radii or 73,387,747​¹⁰⁰⁄₆₆₀ miles. In his Opus Majus, Roger Bacon cited Al-Farghānī's distance to the stars of 20,110 Earth radii, or 65,357,700 miles, from which he computed the circumference of the universe to be 410,818,517​³⁄₇ miles. Clear evidence that this model was thought to represent physical reality is the accounts found in Bacon's Opus Majus of the time needed to walk to the Moon and in the popular Middle English South English Legendary, that it would take 8,000 years to reach the highest starry heaven. General understanding of the dimensions of the universe derived from the nested sphere model reached wider audiences through the presentations in Hebrew by Moses Maimonides, in French by Gossuin of Metz, and in Italian by Dante Alighieri.

Philosophical and theological discussions

Philosophers were less concerned with such mathematical calculations than with the nature of the celestial spheres, their relation to revealed accounts of created nature, and the causes of their motion.

Adi Setia describes the debate among Islamic scholars in the twelfth century, based on the commentary of Fakhr al-Din al-Razi about whether the celestial spheres are real, concrete physical bodies or "merely the abstract circles in the heavens traced out… by the various stars and planets." Setia points out that most of the learned, and the astronomers, said they were solid spheres "on which the stars turn… and this view is closer to the apparent sense of the Qur'anic verses regarding the celestial orbits." However, al-Razi mentions that some, such as the Islamic scholar Dahhak, considered them to be abstract. Al-Razi himself, was undecided, he said: "In truth, there is no way to ascertain the characteristics of the heavens except by authority [of divine revelation or prophetic traditions]." Setia concludes: "Thus it seems that for al-Razi (and for others before and after him), astronomical models, whatever their utility or lack thereof for ordering the heavens, are not founded on sound rational proofs, and so no intellectual commitment can be made to them insofar as description and explanation of celestial realities are concerned."

Christian and Muslim philosophers modified Ptolemy's system to include an unmoved outermost region, the empyrean heaven, which came to be identified as the dwelling place of God and all the elect. Medieval Christians identified the sphere of stars with the Biblical firmament and sometimes posited an invisible layer of water above the firmament, to accord with Genesis. An outer sphere, inhabited by angels, appeared in some accounts.

Edward Grant, a historian of science, has provided evidence that medieval scholastic philosophers generally considered the celestial spheres to be solid in the sense of three-dimensional or continuous, but most did not consider them solid in the sense of hard. The consensus was that the celestial spheres were made of some kind of continuous fluid.

Later in the century, the mutakallim Adud al-Din al-Iji (1281–1355) rejected the principle of uniform and circular motion, following the Ash'ari doctrine of atomism, which maintained that all physical effects were caused directly by God's will rather than by natural causes. He maintained that the celestial spheres were "imaginary things" and "more tenuous than a spider's web". His views were challenged by al-Jurjani (1339–1413), who maintained that even if the celestial spheres "do not have an external reality, yet they are things that are correctly imagined and correspond to what [exists] in actuality".

Medieval astronomers and philosophers developed diverse theories about the causes of the celestial spheres' motions. They attempted to explain the spheres' motions in terms of the materials of which they were thought to be made, external movers such as celestial intelligences, and internal movers such as motive souls or impressed forces. Most of these models were qualitative, although a few incorporated quantitative analyses that related speed, motive force and resistance. By the end of the Middle Ages, the common opinion in Europe was that celestial bodies were moved by external intelligences, identified with the angels of revelation. The outermost moving sphere, which moved with the daily motion affecting all subordinate spheres, was moved by an unmoved mover, the Prime Mover, who was identified with God. Each of the lower spheres was moved by a subordinate spiritual mover (a replacement for Aristotle's multiple divine movers), called an intelligence.

Renaissance

Thomas Digges' 1576 Copernican heliocentric model of the celestial orbs

Early in the sixteenth century Nicolaus Copernicus drastically reformed the model of astronomy by displacing the Earth from its central place in favour of the Sun, yet he called his great work De revolutionibus orbium coelestium (On the Revolutions of the Celestial Spheres). Although Copernicus does not treat the physical nature of the spheres in detail, his few allusions make it clear that, like many of his predecessors, he accepted non-solid celestial spheres. Copernicus rejected the ninth and tenth spheres, placed the orb of the Moon around the Earth, and moved the Sun from its orb to the center of the universe. The planetary orbs circled the center of the universe in the following order: Mercury, Venus, the great orb containing the Earth and the orb of the Moon, then the orbs of Mars, Jupiter, and Saturn. Finally he retained the eighth sphere of the stars, which he held to be stationary.

The English almanac maker, Thomas Digges, delineated the spheres of the new cosmological system in his Perfit Description of the Caelestiall Orbes … (1576). Here he arranged the "orbes" in the new Copernican order, expanding one sphere to carry "the globe of mortalitye", the Earth, the four classical elements, and the Moon, and expanding the sphere of stars infinitely to encompass all the stars and also to serve as "the court of the Great God, the habitacle of the elect, and of the coelestiall angelles."

Johannes Kepler's diagram of the celestial spheres, and of the spaces between them, following the opinion of Copernicus (Mysterium Cosmographicum, 2nd ed., 1621)

In the sixteenth century, a number of philosophers, theologians, and astronomers—among them Francesco Patrizi, Andrea Cisalpino, Peter Ramus, Robert Bellarmine, Giordano Bruno, Jerónimo Muñoz, Michael Neander, Jean Pena, and Christoph Rothmann—abandoned the concept of celestial spheres. Rothmann argued from observations of the comet of 1585 that the lack of observed parallax indicated that the comet was beyond Saturn, while the absence of observed refraction indicated the celestial region was of the same material as air, hence there were no planetary spheres.

Tycho Brahe's investigations of a series of comets from 1577 to 1585, aided by Rothmann's discussion of the comet of 1585 and Michael Maestlin's tabulated distances of the comet of 1577, which passed through the planetary orbs, led Tycho to conclude that "the structure of the heavens was very fluid and simple." Tycho opposed his view to that of "very many modern philosophers" who divided the heavens into "various orbs made of hard and impervious matter." Edward Grant found relatively few believers in hard celestial spheres before Copernicus and concluded that the idea first became common sometime between the publication of Copernicus's De revolutionibus in 1542 and Tycho Brahe's publication of his cometary research in 1588.

In his early Mysterium Cosmographicum, Johannes Kepler considered the distances of the planets and the consequent gaps required between the planetary spheres implied by the Copernican system, which had been noted by his former teacher, Michael Maestlin. Kepler's Platonic cosmology filled the large gaps with the five Platonic polyhedra, which accounted for the spheres' measured astronomical distance. In Kepler's mature celestial physics, the spheres were regarded as the purely geometric spatial regions containing each planetary orbit rather than as the rotating physical orbs of the earlier Aristotelian celestial physics. The eccentricity of each planet's orbit thereby defined the radii of the inner and outer limits of its celestial sphere and thus its thickness. In Kepler's celestial mechanics, the cause of planetary motion became the rotating Sun, itself rotated by its own motive soul. However, an immobile stellar sphere was a lasting remnant of physical celestial spheres in Kepler's cosmology.

Literary and visual expressions

"Because the medieval universe is finite, it has a shape, the perfect spherical shape, containing within itself an ordered variety....
"The spheres ... present us with an object in which the mind can rest, overwhelming in its greatness but satisfying in its harmony."

C. S. Lewis, The Discarded Image, p. 99

Dante and Beatrice gaze upon the highest Heaven; from Gustave Doré's illustrations to the Divine Comedy, Paradiso Canto 28, lines 16–39

In Cicero's Dream of Scipio, the elder Scipio Africanus describes an ascent through the celestial spheres, compared to which the Earth and the Roman Empire dwindle into insignificance. A commentary on the Dream of Scipio by the Roman writer Macrobius, which included a discussion of the various schools of thought on the order of the spheres, did much to spread the idea of the celestial spheres through the Early Middle Ages.

Nicole Oresme, Le livre du Ciel et du Monde, Paris, BnF, Manuscrits, Fr. 565, f. 69, (1377)

Some late medieval figures noted that the celestial spheres' physical order was inverse to their order on the spiritual plane, where God was at the center and the Earth at the periphery. Near the beginning of the fourteenth century Dante, in the Paradiso of his Divine Comedy, described God as a light at the center of the cosmos. Here the poet ascends beyond physical existence to the Empyrean Heaven, where he comes face to face with God himself and is granted understanding of both divine and human nature. Later in the century, the illuminator of Nicole Oresme's Le livre du Ciel et du Monde, a translation of and commentary on Aristotle's De caelo produced for Oresme's patron, King Charles V, employed the same motif. He drew the spheres in the conventional order, with the Moon closest to the Earth and the stars highest, but the spheres were concave upwards, centered on God, rather than concave downwards, centered on the Earth. Below this figure Oresme quotes the Psalms that "The heavens declare the Glory of God and the firmament showeth his handiwork."

The late-16th-century Portuguese epic The Lusiads vividly portrays the celestial spheres as a "great machine of the universe" constructed by God. The explorer Vasco da Gama is shown the celestial spheres in the form of a mechanical model. Contrary to Cicero's representation, da Gama's tour of the spheres begins with the Empyrean, then descends inward toward Earth, culminating in a survey of the domains and divisions of earthly kingdoms, thus magnifying the importance of human deeds in the divine plan.