Opiates or opioid analgesics are a group of substances that bind to opioid receptors in the nervous system and other tissues. They are mainly used for their analgesic activity, but it is important to remember that they have many other effects throughout the body. The body also naturally creates its own opioid ligands such as endorphins and enkephalin. Currently, there are four known receptor types: μ, κ, δ and σ.
For the most part, the terms opioids and opiate are used synonymously. Opiates are synthetic drugs derived from opium. The term opioid refers to all drugs (synthetic, semi-synthetic, and natural) with properties similar to opium.
Mechanism of Action
Central and peripheral opioid receptors are coupled to inhibitory G-proteins. The inhibition of adenylate cyclase activity lowers Ca2+ and results in hyperpolarization.
The effect on receptor types
The effects on μ receptors include supraspinal analgesia, respiratory depression, miosis, and euphoria.
The effects of κ receptors include spinal analgesia, sedation, and miosis.
δ-receptors induce cardiovascular stimulation and mydriasis and can cause dysphoria and hallucinations.
Classification of agonists and antagonists
Depending on their interaction with the receptors, opioids are classified as pure agonists, partial agonists, mixed agonist-antagonist, or pure antagonists:
- Pure agonists bind to μ receptors and have maximum effect depending on dosage. Among them are morphine, fentanyl and pethidine.
- Partial agonists, i.e. buprenorphine, have a partially agonistic and antagonistic effect. They have a ceiling effect meaning that from a certain dose on, increasing the dosage will not increase its effect. This is the result of its very high affinity for the μ receptor with lower intrinsic activity than morphine.
- Mixed agonists-antagonists like pentazocine are antagonists at the μ receptor and agonists at the κ receptor with high intrinsic activity. Due to their antagonistic effect, they can block agonists from the receptor and reverse their effects.
- Pure antagonists are competitive antagonists that bind to and block all opioid receptors. Among them are naloxone and naltrexone.
Dose-response curve for an agonist and a partial agonist
Central and peripheral effects of opioids
Among the central effects of opioids is the reduction of pain transmission by stimulating opioid receptors. They activate the descending inhibitory system, spinal nociceptive impulses are suppressed and the pain sensation in the limbic system is modulated. Furthermore, opioids have a sedating effect on mental activity and a hypnotic effect. In addition, there are anxiolytic and euphoria-inducing components. By inhibiting the respiratory center and the cough reflex, opioids cause respiratory depression and have an antitussive effect.
Patients frequently experience nausea and vomiting at the beginning of opioid therapy, because of stimulation of the “vomiting center” in the area postrema at the floor of the fourth ventricle. Later on, however, they inhibit vomiting activity and have an antiemetic effect. Miosis (pinpoint pupils) is often associated with opioid use. This is caused by stimulation of the Edinger-Westphal nucleus in the mid-brain causing the sphincter pupillae (musculus sphincter pupillae) to contract.
Peripheral effects include analgesia, delayed gastric emptying due to contraction of the pylorus, reduced gastric motility, and increased tone of the smooth musculature of the gastrointestinal tract. In addition, the tone of the bladder muscle and bladder contractor muscle is increased. Histamine release is also common, causing intense itching.
Contraindications to and Interactions with Opioids
Relative contraindications to the use of opioids
- Children under the age of 1 year
- Respiratory insufficiency, i.e. asthma
- Increased intracranial pressure
- Hypotension or hypovolemia due to the blood pressure-reducing effects of the substances
- Opioid dependence
- Gallbladder and urinary tract diseases– the spastic contraction of the urinary sphincter may lead to urinary retention
- Pancreatitis as the sphincter tone is increased and there is a risk of secretion build-up
- Obstructive and inflammatory gastrointestinal diseases as the tone of the smooth musculature increases, bringing about the risk of spasms and perforation
- Ileus – here is a risk of perforation as well
Note: During pregnancy and while breastfeeding, the indication must be strictly defined.
Interactions between opioids and other drugs
There are interactions between opioids and CNS depressants such as hypnotics, phenothiazines, tranquilizers, and especially alcohol. They enhance the sedating effects of opioids and may lead to life-threatening respiratory depression.
Motility inhibitors enhance the constipating effects of opioids and cimetidine slows down the break-down of morphine.
Indications for Opioids
Indications for the use of opioids are severe and extreme pain (nociceptive type pain), i.e. in the context of surgeries and tumors. Opioid analgesics are also especially suited for treating pain in cases of acute myocardial infarction and acute pulmonary edema because of their psycho-sedating effects.
The WHO ladder governing the use of opioids
The WHO ladder is used for the treatment of chronic pain and was originally created for the treatment of tumors. It is, however, also being applied for the treatment of chronic musculoskeletal pain if NSRA drugs are contraindicated or if they do not provide sufficient pain relief.
- Step 1: Non-opioid analgesics
- Step 2: Non-opioid analgesics plus mild opioids such as tramadol and tilidine
- Step 3: Non-opioid analgesics plus strong opioids such as morphine, hydromorphone and oxycodone
- Step 4: Invasive techniques such as epidural injection, peripheral local anesthesia and ganglion block
Dependence and the development of opioid tolerance are promoted if opioids are only administered during pain peaks. Therefore, pain management should consist of basic medication with retarding products and on-demand medication with fast-acting substances if pain peaks occur.
Retarding products are frequently applied as patches that need to be changed every 72 hours. It should be noted that it takes some time for these patches to develop their full effect and that this effect continues on for up to 16 hours after the patch has been removed.
Substances and Their Use with Opioids
Low-potency opioid analgesics
Low-potency opioids such as tilidine, dihydrocodeine, codeine and tramadol are not subject to the Controlled Substances Act and are administered for relieving moderate to severe pain. In comparison to morphine, they have lower efficacy, meaning they have lower analgesic (relative) potency (RP < 1).
If the dosage of low-potency opioids is increased to a certain point, pain relief equal to morphine can be achieved. This is referred to as maximum attainable response (analgesia). Any further increase in dosage would only result in stronger side effects while the analgesic effect cannot be increased. This is not the case with high-potency opioids.
Tramadol has 0.1 to 0.2 times the analgesic potency of morphine. Its most severe side effects are nausea and vomiting, whereas constipation and respiratory depression rarely occur. The effects of tramadol last four to six hours and it can be taken orally or be administered intravenously, intramuscularly or rectally.
Dihydrocodeine and codeine have a relative potency of 0.3 and are used as antitussives because of their strong cough suppressant properties. Its effect lasts approximately eight to twelve hours and it is administered orally.
The most common side effect of codeine is headache. The most common side effect of dihydrocodeine is constipation.
Tilidine has an analgesic potency of 0.2 and its effect lasts approximately three hours. Tilidine is metabolized to nortilidine via hepatic conversion. Tilidine is available in fixed combination with the opioid antagonist naloxone.
If a normal dose of this product is taken orally, naloxone is inactivated by the first-pass effect in the liver and nortilidine becomes effective. If it is injected in an abusive manner, however, naloxone will become effective as the hepatic inactivation of naloxone is delayed. As opioid receptor antagonist, it prevents the addiction-causing effect as well as the dreaded respiratory depression.
Note: The fixed combination tilidine-naloxone is not subject to the Controlled Substances Act just like the other low-potency opioids.
Pentazocine and pethidine only play a role in post-operative analgesia. Both have short duration of action and may cause hallucinations. Even though they are mild opioids, they are subject to the Controlled Substances Act.
Morphine is quickly absorbed after oral administration. The first-pass effect in the liver is very high with 30 – 50 %. Furthermore, morphine undergoes conjugation with glucuronic acid forming 3-glucuronide and 6-glucuronide. While 3-glucuronide has no analgesic effects, the analgesic effect of 6-glucuronide is very high. The half-life is between two and three hours, which is why morphine is administered two to three times a day. If pain peaks occur, additional morphine solution may be administered.
For patients whose pain cannot be sufficiently relieved by administering oral morphine, continuous intrathecal or epidural morphine administration is suitable. It is applied via a subcutaneous reservoir or a subcutaneous computer-controlled pump. Indications are, for instance, abdominal metastases and pain in the lower extremities with syringomyelia, spinal tumors, and traumatic paraplegia.
As buprenorphine is highly lipophilic, it is well absorbed and is 40 times more potent than morphine. It has, however, poor bioavailability due to its high first-pass effect, which is why the usual administration is parenteral, transdermal or sublingual. Due to its high affinity to opioid receptors, it is resistant to antagonism by naloxone.
Oxycodone has a similarly good analgesic effect compared to morphine and is especially used in orthopedics, i.e. following partial knee prosthetics.
Opioids and Anesthesia
Within the context of anesthesia, it is primarily the μ receptor that is responsible for the opioid effects but the κ receptor is also responsible to a lesser degree. Stimulating the μ1 receptor leads to pronounced spinal and supraspinal analgesia but also to simultaneous respiratory depression via the μ2 receptor. No pure μ1 agonists have been found so far. Stimulating the κ receptor causes spinal analgesia and sedating side effects via receptors in the cortex.
Fentanyl, alfentanil, sufentanil, and remifentanil are pure and selective μ agonists that are used for intravenous (as well as total intravenous anesthesia [TIVA]) and balanced anesthesia. Their benefits include good analgesic efficacy, low hemodynamic influence and antagonist ability. Furthermore, there is no liver or kidney toxicity and they do not trigger malignant hyperthermia. Even though they improve the tolerance of endotracheal intubation, they may lead to thorax rigidity, causing problems with assisted ventilation.
They reduce respiratory center CO2 sensitivity leading to respiratory depression. This can result in hypercapnia with significant increase in cerebral perfusion and intracranial blood volume. Another side effect of opioids is increased tone of the bronchial musculature resulting in increased respiratory resistance. Other disadvantages regarding anesthesia with opioids are insufficient reflex reduction, postoperative nausea, and the absence of amnesia with a relatively prolonged wake-up phase.
|Analgesic potency (morphine = 1):||125||30||1000||450 – 900|
|Duration of action:||20 – 30 min.||15 – 20 min.||30 min.||2 – 3 min.|
|Metabolism:||Hepatic metabolism, renal excretion||Hepatics metabolism, renal excretion||Hepatic metabolism||Metabolism via plasma esterases, renal excretion|
|Remarks:||Highly lipophilic||Not as highly lipophilic = less likely to accumulate – suitable for short procedures||Similar to fentanyl||Continuous administration is necessary due to its short half-life – suitable for total intravenous anesthesia in combination with propofol|
Note: Fentanyl, alfentanil, sufentanil, and remifentanil are not considered narcotics as they do not cause a general depression of neuronal activity.
Treatment of Dyspnea with Opioids in Palliative Medicine
A commonly observed problem during the terminal stage of many diseases is dyspnea. And opioids may be administered for symptomatic relief. Drugs such as morphine are administered nasally or subcutaneously.
The receptor-specific opioid effects may be competitively canceled out either completely via pure antagonists such as naloxone, or partially via mixed agonists-antagonists such as nalbuphine.
Antagonists are used in order to eliminate opioid-induced respiratory depression due to an absolute or relative overdose or in the context of postoperative reversal of opioid effects.
The administration of naloxone should be titrated in order to cancel out the respiratory depression while maintaining analgesia. There is the risk of tachycardia and increase in blood pressure. Naloxone has a short duration of action of 30 minutes, after which respiratory depression may rebound. Patients must be carefully monitored for a sufficient period of time after the antagonist administration.
Nalbuphine is a mixed agonist-antagonist meaning its intrinsic activity at the μ receptor is significantly less than that of pure agonists used for anesthesia. Its analgesic effect, on the other hand, is mainly mediated by its agonist activity at the κ-receptors and its duration of action is approximately two to three hours.
The classic opioid overdose triad of symptoms is: respiratory depression with a respiratory rate of two to four breaths per minute, coma, and miosis. Immediate treatment is essential in the form of assisted ventilation and titrated administration of the antagonist naloxone.
Note: because opioid abuse is frequently combined with alcohol, sedatives or psycho-stimulants, the symptoms may not always be clear (you may be dealing with miosis for instance), naloxone may be used as a diagnostic tool when the cause of toxicity is unknown.
Opiate Withdrawal Syndrome
Opiate dependence with withdrawal symptoms commonly develop with heroin use but also occur with prescription opioid use.
The cause of opioid dependence is the development of tolerance. The reason for the adjustment to these drugs is pharmacodynamic tolerance based on increased adenylyl cyclase activity. Signs of developing tolerance are an individual’s diminished response to the drug as well as the shortened duration of action that has to be compensated by increasing the dosage.
Withdrawal symptoms include bone pain and muscle aches, fever, tachycardia, insomnia, and psychosomatic restlessness. Atypical symptoms, however, are symptoms of psychosis and delirium.
Withdrawal symptoms are treated with sedating benzodiazepines with long half-time such as diazepam and sedating tricyclic antidepressants. Ultra-rapid detoxification (URD) that takes place under anesthesia with high doses of opiate antagonists such as naloxone and naltrexone is controversial.
Opiate Replacement Therapy
For many opiate addicts, replacement therapy may facilitate psychosocial integration, reduce criminal activity for the purpose of obtaining drugs and lower the risk of acquiring HIV and hepatitis that accompanies drug use. In most cases, the replacement drug is methadone.
Methadone is a synthetic racemate, only the L-form is effective (levomethadone). Due to its long half-life of 24 – 48 hours, there is no typical “rush” effect, which is why it is so suitable for replacement therapy.
Levo-alpha-acetylmethadol or LAAM has an even longer half-life and does not have to be taken more than three times per week. The benefits are fewer fluctuations minimizing the risk of withdrawal symptoms and better bridging weekends as daily physician-patient contact is not necessary.
Loperamide does not cross the blood-brain barrier into the brain as its epithelial cells immediately pump it back into the blood. Loperamide increases the pendulum movement of the gastrointestinal muscles and inhibits GI propulsion. Furthermore, it may reduce loss of enteral fluids.
An indication for loperamide is a temporary measure in cases of traveler’s diarrhea, caused by either a viral or bacterial infection. It is not, however, indicated in cases of functional diarrhea due to toxins produced by bacteria. The antidiarrheal effect of loperamide is cancelled out by naloxone.
Loperamide is contraindicated in children under the age of two as central morphine-like side effects have been observed and there have been some reports of ileus.
Racecadotril, on the other hand, is suitable and has been approved for the treatment of babies and infants with diarrhea. It is administered orally and inhibits the break-down of enkephalins, thus reducing the secretion of water and sodium in the intestinal epithelium.
Fun fact: Opium tincture used to be the standard remedy for traveler’s diarrhea but is no longer used because of the Controlled Substances Act.
The answers are below the references.
- A 45-year old man is found unconscious by a passer-by. She alarms emergency personnel. The emergency physician examines the man and finds pinpoint pupils and several abscessed track marks in the crook of his right arm and on his right hand. The respiratory rate is only three breaths per minute. As the physician suspects opioid intoxication, he administers naloxone and the man comes to relatively fast. He is stable. How should the physician proceed next?
- The man should be taken to the hospital because of the short half-time of
- Titrated naloxone administration should be continued until the man has sobered up completely and can go home.
- The man’s wishes should be respected and he should be left alone.
- The police should be notified because of the unlawful possession and use of
- The man should be intubated as he may immediately relapse into respiratory
- A 20-year-old man is involved in a bad car accident. The emergency physician arrives on scene and administers intravenous fentanyl to relieve the pain. As the circumstances of the accident are unclear, emergency personnel conduct a sweat test for drugs five minutes later. All fields are negative, even the one for opiates. What is the reason for this field to be negative even though the patient has received fentanyl?
- Fentanyl does not yet show up in sweat after five minutes.
- The test must be faulty.
- Fentanyl is not an opiate.
- Due to its high lipophilia, fentanyl does not transfer into sweat.
- The patient has to undergo drug replacement therapy with naloxone.
- What does the term ceiling effect describe with regard to administering partial opioid receptor agonists such as buprenorphine?
- From a certain dose on, the antagonistic effect exceeds the agonistic effect.
- The effect is always the same, independent of the dose given.
- From a certain dose on, increasing the dosage will not increase the effect.
- Psychotic symptoms occur during replacement therapy if the dosage is too
- Individual dosing, only the constipating effect of buprenorphine is cancelled out by the antagonistic component.