GENERAL
Opioids are substances similar to morphine that have been used for centuries to provide pain relief. The term “opioid” derives from the word “opium”, obtained from the poppy flower. There are natural, synthetic and semi-synthetic opioids. It has been known since 1975 that the human body endogenously produces its own opioids: enkephalins, endorphins and dynorphins. There are opioid receptors along the whole human body which, when activated by opioids, cause analgesia but also other adverse actions.
Opioids are divided in opioid agonists and opioids with mixed action, agonist and antagonist, depending on how they behave to the opioid receptor with which they come in contact.
Another distinction has to do with the onset of action and the duration of action of opioids. Each opioid has its own unique potency, onset action and duration of action.
Opioids can be administered through different routes: orally, transdermally, subcutaneously, intravenously, absorbed from the oral or nasal mucosa, rectally (suppository) and epidurally or subarachnoidally (central nervous system).
OPIOID AGONISTS
Most opioids belong to the group of agonists, which are connected with opioid receptors located within cells and motivate the response to the receptors’ stimulation. Opioid agonists produce action, whereas antagonists block the receptor’s action. Common opioid agonists are morphine, phentanyl and oxicodone (the last one is not available in Greece).
OPIOID AGONISTS/ ANTAGONISTS
There are opioids that are partially agonists and other that are mixed agonists/ antagonists. Mixed agonists/ antagonists are characterized by the ceiling phaenomenon meaning that the analgesic result cannot improve beyond a certain point and despite the increase of the drug dose.
Such drugs are buprenorphine , butorphanol , nalbuphine and pentazocine. Combination products are pentazocine/naloxone and buprenorphine/naloxone.
Opioids with mixed action should not be taken simultaneously with opioid agonists in order to avoid the withdrawal phaenomenon that might occur as a result of the neutralization of agonists’ action by antagonists.
Opioid withdrawal symptoms:
• Sweating
• Running nose
• Abdominal cramps
• Diarrhea
• Nervousness
• Agitation
• Τachycardia
• Paraesthesias
RAPID ONSET OPIOIDS
Rapid onset opioids are drugs containing some opioid in pure form, or are combination of an opioid and non-opioid, such as paracetamol (acetaminophen ) or ibuprophane (ibuprofen).
Rapid onset opioids have limited duration of action. Their action usually starts within 15-30 minutes after their administration, with the maximum of their action occurring within 1-2 hours. Their action duration is limited to about 4 hours.
They are an effective option for severe acute pain (postoperative or pain that may last only a few days and be resistant to milder analgesics) and for paroxysmal pain (pain with sudden paroxysmal onset and short duration), chronic benign or malignant pain of patients who are already on slow-release long-acting opioids .They are not indicated for long-term pain treatment because their action lasts approximately 4 hours and their dose would have to be repeated 5-6 times daily without the patient having a stable analgesic result. However, they can be used as a response test to opioids before starting treatment with slow-release long-acting opioids.
Their most important clinical use is in the treatment of severe paroxysmal pain of patients already receiving slow-release long-acting opioids, where indeed they offer satisfactory stable analgesia but at some points during the 24hour-day they present sudden pain exacerbation and need the strong action of some rapid-acting short-duration opioid for their immediate relief.
Strong opioids with rapid action onset and combined with non-opioids are note available in Greece. Such drugs abroad are:
• oxycodone with acetaminophen
• oxycodone with aspirin
• oxycodone with ibuprofen
• hydrocodone with acetaminophen
• hydrocodone with ibuprofen
STRONG RAPID-ACTING OPIOIDS
The only agent with rapid onset available in Greece is phentanyl. It is available in various forms differing as for the way phentanyl is absorbed by the organism. It can be absorbed in the following ways:
• from the renal epithelium by nasal spraying
• from the oral mucosa with per os tablet
• from the oral mucosa with sublingual tablet
• from oral mucosa with lozenge (lollipop)
The fastest peak of Fentanyl concentration is achieved through renal epithelium by spraying (13min), whereas the slowest concentration is achieved with transmucosal lozenge (91min). The peak concentration of the drug orally or sublingually takes almost the same (47 and 49 min respectively). Duration of the therapeutic result is another feature that should be taken into account.
The ideal rapid onset opioid administered for paroxysmal pain is the one having rapid onset of action and short action duration, exactly as happens with paroxysmal pain. Prolonged action is not desirable because it loads the organism with an additional drug dose, when already taking controlled-release opioids.
The duration of rapid onset Fentanyl action is:
• 56 min, with nasal spraying through the renal epithelium
• ~120 min, through the oral mucosa with per os tablet
• ~120 λεπτά, through the oral mucosa with sublingual tablet
• ~ 4 hours, through oral mucosa with lozenge (lollipop)
LONG-ACTING OPIOIDS
They are administered to patients with chronic benign and malignant pain, which is not relieved with drugs or combinations of drugs from other groups or interventional therapies. Their action is prolonged due to their long half-life time or their slow controlled release in the body, based on specific technology. Oral long-acting opioids are administered every 12 hours, while transdermal opioid administration takes place every 72 hours with the application of skin patches (adhesive transdermal delivery system).
Long-acting opioids are the following:
• morphine sustained release (available in Greece)
• oxycodone sustained release
• fentanyl transdermal system (available in Greece)
• methadone (available in Greece)
• oxymorphone
TAPENTADOL
It is a new oral opioid, not yet available in Greece, that has been approved for the treatment of moderate to severe acute pain. Tapentadol acts as an agonist to opioid receptors and also inhibits the reuptake of the neurotransmitter called norepinephrin. This double action limits pain signal transmission to the ascending and descending pain pathway. Tapentadol may present a better profile than other opioids with regard to adverse gastrointestinal side-effects.
MILD OPIOIDS
TRAMADOL AND TRAMADOL COMBINED WITH PARACETAMOL
They are prescribed drugs for the treatment of moderate to severe pain. Their combination with paracetamol is more effective than monotherapy with either of the two drugs alone. The Tramadole mode of action is similar to Tapentadol. It acts as an agonist to opioid receptors and also inhibits the reuptake of the neurotransmitter called norepinephrin. This double action limits pain signal transmission to the ascending and descending pain pathway. It has no anti-inflammatory action and has no negative cardiovascular effect. It does not cause gastrorrhagia (stomach haemorrhage), but its dose should be limited in patients with liver and kidney dysfunction. Maximum daily dose for patients without limitations are 400 mg for the young adults and 300 mg for the elderly, divided in equal doses. Special caustion is needed when the drug is combined with selective serotonine reuptake inhibitors (SSRIs), tricyclic antidepressants and some antipsychotic drugs, due to the risk of serotonergic syndrome which is lire threatening.
MILD OPIOIDS
• codeine – paracetamol combination
• tramadole
• slow release tramadole
OPIOID SIDE-EFFECTS
Α. CENTRAL NERVOUS SYSTEM
• euphoria
• drowsiness, sedation, sleep disorders, illusions
• potential reduction of psychomotor activity
• distress, agitation, dizziness, spasms
• hyperalgesia
Β. RESPIRATORY SYSTEM
• respiratory suppression due to overdosing
• pain reduction by other agents my convert a previously normal dose into toxic and cause respiratory suppression
C. EYES
• pupilar miosis
D. GASTROINTESTINAL TRACT
• Νausea, vomiting, consipation
• Delayed gastric emptying
Ε. URINARY TRACT
• Urinary retention
F. ENDOCRINE SYSTEM
• Hormone dysfunction
• Sexual dysfunction
G. CARDIOVASCULAR SYSTEM
• Reduced arterial blood pressure
• Reduction of heart rate
• Peripheral oedema
Η. ΜYOSLELETAL SYSTEM
• Muscle stiffening (sclerosis) and contractions
• Osteoporosis
I. SKIN
• Pruritus
Ι. IMMUNE SYSTEM
• Potential suppression of the immune system
Κ. GESTATION AND LACTATION
• All opioids pass through the placenta
• Neonatal sedation if administered during gestation
• No teratogenesis has been reported
• Used with caution during breastfeeding
