Narcotic analgesics are natural (plant and animal) drugs of semi-synthetic and synthetic origin. It has a significant analgesic effect with a predominant effect on the CNS and the ability to cause mental and physical dependence (drug addiction). Most people who become addicted to codeine start using the drug for medical reasons. Signs of codeine addiction are very similar to other opioids. Improper use can lead to various problems, including death, if large doses are taken.
Epidemiology and Pharmacological Activity
An estimated thirty-three million people use codeine each year; approximately four-and-a-half million Americans reported nonmedical usage of prescription painkillers, including codeine, according to the 2018 National Survey on Drug Use and Health. Opioids were included in 2019 to 49,860 fatal overdose episodes (70.6% of all drug overdose deaths) (Andrzejowski & Carroll, 2016). Its pharmacological effect can be antipruritic, analgesic (opioid), and anti-diarrheal. Analgesic activity is caused by the excitation of opiate receptors in different parts of CNS and peripheral tissues, leading to stimulation of the antinociceptive system and a change of emotional perception of pain. The central anti-cough effect is associated with suppression of the cough center at the bowel level.
Optimization of opiate receptors in the intestine causes relaxation of smooth muscles, decreased peristalsis, and spasm of all sphincters. It is quickly absorbed after oral ingestion; the binding to plasma proteins is insignificant. The drug is bio-transformed in the liver, with 10% of the demethylation being converted to morphine. T1/2 is 2.5-4 hours. It is excreted by the urine: 5-15% as codeine and 10% as morphine and its metabolites. The analgesic effect develops 10-30 minutes after v/m and p/c and 30-60 minutes after enteral administration (Fortenberry et al., 2019). The maximum effect is achieved 30-60 min after p / m introduction and 1-2 h after enteral application. The duration of analgesia – is 4 hours, and blockade of the cough reflex – is 4-6 hours.
Medication Interaction
When simultaneous use with drugs with CNS depressant effect (including opioid analgesics, barbiturates, benzodiazepines, clonidine), enhancement of codeine action is possible. In concomitant use with morphine derivatives, it is reasonable to improve the inhibitory impact on the respiratory center. With ibuprofen, the analgesic activity improves; with carbamazepine, the analgesic effect may increase, apparently due to the higher forms of the codeine metabolite normorphine, which has a stronger effect (Cairns et al., 2016). When used concomitantly with quinidine, the analgesic properties of codeine are reduced or almost disappear. When used concomitantly, codeine increases the effect of ethanol on psychomotor functions.
Production and Sale of Codeine
Opium poppy varieties are characterized by a well-developed milk-vessel system that yields a large milk sap and large bolls. They are cultivated to produce opium (the dried milk juice of the poppy). Opiates such as codeine are mainly obtained by extraction from the opium poppy. Besides, the enzymatic production of opiates in microbes has been investigated, and recently in yeast, the whole biosynthesis of drugs from a simple carbon source has been carried out. The usefulness of poppy for pharmaceuticals is that codeine, morphine, and papaverine extracted from poppy capsules are used to produce analgesics, sleeping pills, anti-cough, and antispasmodics (Cairns et al., 2016). Narcotic substances are also obtained from the same morphine and codeine, which is why poppy cultivation is under state control.
The Health and Safety Code bans the trade, transportation, furnishing, giving, or importer of certain controlled substances in California. The statute extends to prescription drugs such as codeine-oxycodone (OxyContin) and hydrocodone (Vicodin).
A felony conviction is sanctioned by up to nine years of incarceration in the state and a fine of up to twenty thousand dollars. In the example of North Carolina, the state has legal over-the-counter sales of codeine, such as the brand Cheratussin, which contains 10 mg of codeine and 100 mg of guaifenesin per 5 milliliters (Cairns et al., 2016). Meanwhile, Schedule V substances can only be sold without a prescription by registered pharmacists. Thus, the assortment of items pharmacists can offer people who want to relieve pain will be decreased. Drugstores are allowed to dispense over-the-counter medications, including codeine, that are not marked as prescription-only medications.
Side Effects and Overdose
Side effects caused by codeine are divided into more and less severe. The more acute include: the development of intense respiratory depression, slowed heart rate, weak pulse, hypotension, mental confusion, hallucinations, epilepsy, and difficulty urinating. Less severe ones embody sedation, dizziness, miosis, dry mouth, nausea, vomiting, abdominal pain, constipation, sweating, and minor skin rashes. Codeine used to be widely applied as an analgesic, especially in children, because it was believed to cause fewer aftereffects than other opioids. However, the results of numerous studies do not support this view (Tay et al., 2018).
In particular, codeine and morphine have been shown to cause the same number of reactions with equal severity in equipotent doses. Although there is no or decreased clinical efficacy for pain relief, side effects associated with codeine administration may be noted for some time. Even without being transformed into morphine, codeine molecules themselves can lead to their development.
Genetic polymorphism of cytochrome CYP2D6 is the cause of variability of clinical effects of codeine: from the complete absence of reaction to its excessive severity with possible lethal outcome. The ideal option when prescribing codeine would be to perform genetic testing of patients to rule out ordering this drug to slow and ultrafast metabolizers. However, such tests are available only in limited quantities and for research studies (Tay et al., 2018).
Considering the above, scientists concluded that the introduction of codeine into the drug should be considered a complicated and unreliable route of morphine delivery into the body. Investigations have also shown that repeated administration of codeine, even in normal doses, leads to the cumulation of morphine. On the one hand, this can improve the clinical efficacy of the drug. On the other hand, it can direct to an increase in its side effects. Dependence caused by codeine can cause toxic impacts due to the overuse of those drugs with which it is combined.
Codeine, like other opioids, can be addictive and physically dependent. Codeine overdose is one of the reasons for lethal outcomes. It occurs due to poisoning caused by chronic drug abuse or combining opiates with other psychoactive substances, alcohol, or strong medicines. The main symptoms of overdose are: cold, clammy sweat, confusion, dizziness, drowsiness, decreased blood pressure, nervousness, fatigue, miosis, bradycardia, sharp weakness, slow labored breathing, hypothermia, and anxiety (Tay et al., 2018).
Dry mouth, delirium psychosis, intracranial hypertension, hallucinations, muscle rigidity, seizures, and in severe cases – respiratory arrest and coma may also be observed. Moreover, excessive doses can lead to loss of consciousness and cardiac arrest. Codeine use slows breathing, which in turn reduces the oxygen content of the blood and organs. It can have a devastating effect on organ systems as the heart and brain are particularly sensitive to a lack of oxygen.
Dosage and Expected Effects
Drugs containing codeine have a mild effect, unlike other painkillers. After such remedies enter the shape, they act in the midst of the illness, stopping the coughing. The mechanism of operation of codeine is that the morphine formed from it binds to μ- and κ-opioid receptors in the central nervous system, which supplies the analgesic impact. The oral dosage for adults in pain is 15-60 mg every 3-6 hours; in diarrhea, 30 mg 4 times a day; in cough, 10-20 mg 4 times a day. For children over 12, these applications are respectively 0.5 mg/kg 4-6 times a day, 0.5 mg/kg 4 times a day, and 3-10 mg/kg 4-6 times a day (Tay et al., 2018).
Treatment with the drug is considered appropriate in only a few countries and in limited cases only when other medications have not been effective. Codeine for young children and pregnant and lactating women is inadmissible. It is given intramuscularly in the same measurements as enteral administration (Tay et al., 2018). The highest daily dose must not exceed 120 mg; otherwise, overdose and addiction may occur. Rapid onset of effect characterizes the drug; changes transpire within seconds.
The Codeine Dependence
Codeine-containing drugs can be used in varying amounts to achieve a pleasurable experience. The initial dose is usually from 2 to 5 tablets per day, and after 2 to 3 months of regular use, it may increase to 40 to 50 or even (in some cases) up to 120 pills at 2-3 to 4 doses (Roberts & Nielsen, 2018). This increase is associated with the rapid development of tolerance-specific resistance to the effects of codeine and the need to use inscriptions in increasing quantities to obtain euphoria. In 20-30 minutes after using the medicines, patients get the desired effect: warmth and exhaustion in the body, calmness, even good mood, laziness, and desire to lie down. If taking pills is more than one month, then the activity increases, so there is a desire to engage in current affairs.
The pupils of the users narrow, their eyes are shiny, and the skin becomes warm and dry. Such a pleasant state develops an addiction, and there is a persistent desire to repeat it regularly. With forced breaks of more than 12-24 hours, pleasant sensations are replaced by the opposite – painful, sometimes unbearable. Withdrawal syndrome develops, which is almost impossible to tolerate in home conditions (Roberts & Nielsen, 2018).
In cases of primary codeine addiction, it occurs after 2-4 weeks of daily abuse. In the first phase of retreat, pupils begin to dilate; breathing becomes frequent and shallow. Sweating, nasal congestion, violent yawning, a feeling of ‘goose bumps,’ and short bursts of heat happen. In the second stage, nausea, vomiting, multiple liquid stools, cramping-like abdominal pain, palpitations up to 150 beats per minute, increased blood pressure, and involuntary spastic contractions of the arms and legs muscles occur. The pain syndrome is characterized by a longer duration than during heroin withdrawal. It has a wavelike course and may be additionally complicated by headaches. Anxiety, motor restlessness, inability to sit in one place or lie down, and severe insomnia at night may also appear.
Pathological craving for the use of codeine-containing drugs is expressed in the form of constantly present or arising intrusive thoughts, memories of the application of pills, and vivid night dreams with scenes of use. Patients are irritable, heightened susceptibility to minimal discomfort, and are perceived each time as a stressful situation. The distinctive feature of mental disorders during withdrawal of codeine-containing drugs are memory disorders of a type of fixation amnesia.
Methods of Treatment
The first step at the beginning of treatment is to distance the patient from the outside environment where he can access the drug. The most suitable option for this is hospitalization in a closed drug treatment clinic. Saline solution drips are intended to clean the blood from the products of drug decay and remove toxins from the body. The patient is put on IVs containing saline, glucose, and various absorptive products. This helps to eliminate withdrawal symptoms quickly and makes the patient feel better (Nielsen et al., 2018). It is also useful to use a drug treatment to relieve withdrawal and support the normal functioning of the internal organs. In order to eliminate the symptoms of abnormalities caused by codeine, the patient may be prescribed analgesics, anti-inflammatory tablets, sleeping pills, neuroleptics, and antiemetics.
For codeine addicts, naltrexone-based medications could be administered; they block the brain’s opioid receptors and thus prevent the addict from enjoying the drug. The way to eliminate painful cravings for codeine is always selected on an individual basis. Measures should be aimed at removing mental dependence; psychotherapeutic techniques are a compulsory component of the complex treatment of codeine addiction (Norman et al., 2016). The doctor’s goal is to restore the patient’s mental stability, revive his spiritual world, and recover his lost social skills.
The final stage of codeine dependence treatment is resocialization; in order to incorporate the development created during therapy, the addict should be placed in a rehabilitation center. There he will work with a psychotherapist, people who have been able to recover and start life afresh. All previous efforts will fall apart if physically and spiritually regenerated people find themselves in a society where no one cares about them or only old drug-addict friends are waiting for them to return.
References
Andrzejowski, P., & Carroll, W. (2016). Codeine in paediatrics: pharmacology, prescribing and controversies. Archives of Disease in Childhood-Education and Practice, 101(3), 148-151. Web.
Cairns, R., Brown, J. A., & Buckley, N. A. (2016). The impact of codeine re‐scheduling on misuse: a retrospective review of calls to Australia’s largest poisons centre. Addiction, 111(10), 1848-1853. Web.
Fortenberry, M., Crowder, J., & So, T. Y. (2019). The use of codeine and tramadol in the pediatric population—what is the verdict now?Journal of Pediatric Health Care, 33(1), 117-123. Web.
Nielsen, S., MacDonald, T., & Johnson, J. L. (2018). Identifying and treating codeine dependence: a systematic review. Medical Journal of Australia, 208(10), 451-461. Web.
Norman, I. J., Bergin, M., Parry, C. D., & Van Hout, M. C. (2016). Best Practices and Innovations for Managing Codeine Misuse and Dependence. Journal of Pharmacy and Pharmaceutical Sciences, 19(3), 367-381. Web.
Roberts, D. M., & Nielsen, S. (2018). Changes for codeine. Australian prescriber, 41(1), 2-3. Web.
Tay, E. M., & Roberts, D. M. (2018). A spotlight on the role, use, and availability of codeine and the implications faced. Expert review of clinical pharmacology, 11(11), 1057-1059. Web.