Pain Management

Pain and Pain Management

Assessing, investigating, and treating our patients’ experience of pain is a fundamental part of all anesthesiological work. Expected pain should always be evaluated in the perioperative workup before surgical procedures, and in many cases, pain is the central medical issue both before and after surgery. Patients with known preoperative pain issues often pose a greater postoperative pain challenge and may require special preoperative planning. These patients may also require extended time in a postoperative unit, which is best planned in advance.

Pain is transmitted via nociceptive or neurogenic pain pathways, in addition to psychological and psychosocial factors that influence the perception of pain. Pain perception is always subjective. It varies based on personality traits and the degree of baseline pain sensitivity and is generally exacerbated by depression, anxiety, fear, and distress. Pain can be acute, subacute, chronic, or a combination of these. Chronic pain often leads to severely reduced quality of life. Complex pain management is best handled by multidisciplinary teams specializing in pain. This guide only covers a simplified version of pharmacological pain treatment, with or without regional blocks such as epidural or intrathecal anesthesia. Knowledge and familiarity with various opioids is part of basic anesthesiological competence. Pharmacological therapy is usually administered orally, intravenously, intramuscularly, subcutaneously, or regionally through indwelling catheters. In these catheters, a combination of local anesthetics and an opioid is usually given in continuous infusion. This guide primarily covers pharmacological treatment for adults; for pediatric pain management, specialized literature is recommended. Here you will find a guide for conventional pain treatment, opioid equivalency, basic pharmacokinetics, and various prescriptions for pain treatment administered orally, epidurally, intrathecally, or via patient-controlled analgesia (PCA). Intraoperatively, opioids are typically given intravenously, local anesthetics are used in laparoscopic ports or incisions, and regional blocks are placed when appropriate.

When treating complex pain, a thorough pain analysis must always serve as the basis for treatment. The pain analysis includes an assessment of the severity of the pain, for which there are several scales, such as the VAS scale. In addition, an evaluation of the patient’s quality of life and psychological status is conducted. Nociceptive pain can be divided into somatic and visceral pain. Somatic nociceptive pain primarily comes from the skin, subcutaneous tissue, muscles, and bones. Visceral pain mainly originates from internal abdominal organs, intrathoracic organs, the pleura, or the peritoneum. Neurogenic pain primarily arises from peripheral nerves, the spinal cord, or tumor infiltration into nerve tissue, and it is often inflammation-based. Pain should be assessed regarding whether it is well-localized, diffuse, or radiating. Nociceptive pain can often be described as dull, aching, throbbing, pressing, stabbing, or cutting. Visceral pain is often described as cramping or pressing. Neurogenic pain can be described as burning, tingling, stabbing, itching, cramping, or radiating.

Musculoskeletal pain is usually nociceptive and somatic with an inflammatory component. This pain is suitable for treatment with basic analgesics plus NSAIDs, steroids, or opioids. ASA is unsuitable in cases of bleeding problems or gastritis. In some cases, regional anesthesia, immunosuppression, or other adjuvant treatments such as radiotherapy, physiotherapy, TNS, immobilization (brace/cast), or orthopedic surgery may be used. Physical exercise often has a positive effect on chronic benign pain.

Visceral pain can be perceived as dull, pressing, and severe, often with elements of “referred pain” radiating to the right shoulder (liver) or left shoulder or back (pancreas, spleen, stomach). Treatment may involve opioids, regional blocks (epidural anesthesia), or NSAIDs, and in severe cases, an intrathecal catheter with a mixture of opioids and local anesthetics. NSAIDs should be avoided in cases of gastritis/ulcers and pregnancy.

Pharmacological pain management is based on mild or moderate analgesics, always evaluated based on the expected pain level, which is determined by knowledge of the surgery’s nature, the expected pain, and the patient’s specific situation. Mild analgesics include paracetamol, aspirin, and NSAIDs. NSAIDs are considered unsuitable in cases of risk for kidney failure, increased bleeding tendency, or expected bone formation, such as in reconstructive orthopedic surgery or ENT surgery.

The Critical-Care Pain Observation Tool (CPOT)

Paracetamol

Paracetamol is a basic analgesic with relatively few side effects at therapeutic doses. Typical treatment for adults is 1 g x 4 for up to one week. Paracetamol can also be given if liver transaminases are elevated (< 4 μkat/L), but not if bilirubin, PT, or acute liver failure is present. A combination of paracetamol and NSAIDs such as ibuprofen can relieve mainly musculoskeletal pain of mild to moderate degree, as well as other mild pain. For moderate to moderately severe pain, paracetamol in combination with NSAIDs or codeine may be effective. An alternative to this combination is tramadol as monotherapy or combined with paracetamol and possibly NSAIDs. The anti-inflammatory effect of NSAIDs is best utilized in musculoskeletal pain, where intravenous administration may also be suitable postoperatively, for example, with ketorolac or Toradol. Patients at risk for gastrointestinal discomfort should also receive mucosal protection, such as omeprazole 20 mg x 1.

Opioids

For moderate to severe pain, a morphine-based analgesia is often preferred in perioperative care. For oral administration, paracetamol combined with, for example, oxycodone (OxyContin) can be given as premedication and continued postoperatively. This regimen can be supplemented with an adjuvant drug if neurogenic pain is expected, such as gabapentin (300-1200 mg). Drugs used to treat severe pain often include opioids such as morphine, ketobemidone, oxycodone, fentanyl, or methadone. Further opioids are available for those with a particular interest.

Opioids’ physiological effects include pain inhibition at several levels, including the brain, spinal cord, and peripheral nerves. Opioids provide strong pain relief primarily through opioid receptors in the CNS, via mu-, kappa-, or delta-opioid receptors. Endorphins and enkephalins have natural pain-relieving effects in the CNS, balancing various neurotransmitter substances such as norepinephrine and GABA. Endogenously, dynorphins act on mu and primarily kappa receptors. Enkephalins act on delta receptors. Endorphins primarily act on mu receptors, while beta-endorphins act on both mu and kappa receptors. Morphine provides effective pain relief but can also cause anxiety reduction, euphoria, sedation, somnolence, dreams, cough suppression, nausea, itching, hallucinations, constipation, and respiratory depression. Serious respiratory depression is rare without simultaneous sedation. In overdose, increasing somnolence, motor inhibition, stupor, coma, and respiratory depression occur gradually. Opioids cause pulse and blood pressure to drop, and potent opioids often cause bradycardia. In overdose, breathing becomes slow and inadequate, with miosis, cyanosis, stupor, and eventually cardiovascular collapse. Opioids are the most common cause of overdose deaths related to substance abuse.

Long-term opioid use also affects the neuroendocrine system, inhibiting GnRH, which can lead to decreased FSH, LH, and testosterone. Additionally, CRF is inhibited, causing a decrease in ACTH and cortisol. ADH is also inhibited via KOPR. Opioids stimulate prolactin release. Among opioids’ physiological effects, dose-dependent miosis (pupil constriction) is noteworthy. There is also some histamine release and immune system suppression. Itching is common in overdose. Gastrointestinal motility and secretion are reduced, leading to constipation. This is taken into account in the formulation of Targiniq, which combines an opioid with naloxone. Furthermore, opioids increase pressure in the bile and urinary tracts, making morphine less suitable for bile duct or ureter spasms.

Discontinuation of Opioid Treatment

All opioid treatment should be time-limited to avoid problematic side effects, neuroendocrine effects, and minimize the risk of dependence. After successful surgery, opioid treatment rarely needs to continue for more than three weeks, often not more than one week. Tolerance and withdrawal symptoms can occur after just a couple of weeks of opioid treatment. To avoid dependence, the treatment regimen can be switched, utilizing combinations of anesthetic block techniques and alternating between medium- and strong analgesics. For complex pain management, patients should always be referred to a specialized pain management clinic. Successful treatment often involves interdisciplinary collaboration between multiple specialties, requiring knowledge of the underlying pathophysiology and the patient’s personality and specific needs. When long-term opioid treatment is needed, the dose should be gradually reduced when possible. A suitable dose reduction is about 20% per occasion, spaced a few days apart. In cases where opioid discontinuation is difficult, treatment with clonidine or ketamine may help ease the withdrawal.

Morphine

Maximum blood concentration is reached within 10-20 minutes. The distribution volume is about 3 L/kg with a plasma protein binding of about 35%. Clearance is about 24 ml/min*kg and the half-life is about 2-3 hours. Morphine does not have dose-dependent kinetics. The main metabolites are morphine-3-glucuronide (no analgesic effect) and morphine-6-glucuronide (more potent than morphine itself). Morphine and its metabolites undergo enterohepatic circulation. Elimination of morphine is mainly through glucuronidation and excretion of unchanged morphine in urine is less than 0.1%.

Morphine Basic Therapy and Extra Doses in Pain Treatment

Fentanyl (Fentanyl)

The plasma concentration of fentanyl decreases rapidly after intravenous injection. The elimination process is triphasic with half-lives of about 1 minute, 15 minutes, and 6 hours. The distribution volume in the central compartment is approximately 15 liters, and the total distribution volume is about 400 liters. Secondary peaks in plasma levels may occur.

Fentanyl is bound to plasma proteins by about 80-85%. It is rapidly metabolized mainly in the liver via CYP3A4, primarily through oxidative N-dealkylation. Clearance is about 0.5 l/hour/kg. About 75% of the dose is eliminated within 72 hours. Approximately 10% is excreted unchanged. Half-lives may be prolonged, especially in older individuals or after repeated dosing.

Fentanyl Transdermal

After the first application of the patch, the serum concentration of fentanyl gradually increases. It typically levels off after 12–24 hours and remains relatively constant for the remainder of the 72-hour application period. The serum concentration at steady state is reached at the end of the second 72-hour application and is maintained during subsequent applications of a depot patch of the same size. Due to accumulation, AUC and Cmax values during a dosing interval at steady state are about 40% higher than after a single application. A high variation in plasma concentrations between individuals has been observed.

Alfentanil (Rapifen®)

Alfentanil has sequential distribution half-lives of 0.4–2.2 minutes and 8–32 minutes. The low degree of ionization (11% at pH = 7.4) contributes to rapid but limited distribution in tissues. Reported distribution volumes are 1.27–4.81 liters (distribution volume in the central compartment) and 12.1–98.2 liters (distribution volume at steady state). Plasma protein binding for alfentanil is approximately 92%.

Alfentanil is mainly metabolized in the liver. Only 1% of unchanged alfentanil is found in the urine. The metabolites are inactive, and 70–80% is eliminated via urine.

Alfentanil is rapidly eliminated after intravenous administration. Terminal elimination half-lives have been reported to be 83–223 minutes. Plasma clearance in younger individuals averages 356 ml/min and decreases with age. Only 1% of unchanged alfentanil is found in the urine. Once steady state is reached after infusion, the elimination half-life remains unchanged. Recovery generally occurs quickly after alfentanil treatment is stopped, with no opioid-related aftereffects.

Remifentanil (Ultiva®)

After administration of the recommended doses of remifentanil, the effective half-life is 3-10 minutes. The average clearance of remifentanil in young healthy adults is 40 ml/min/kg, the central distribution volume is 100 ml/kg, and the distribution volume at steady state is 350 ml/kg.

Within the recommended dosing range, the blood concentration of remifentanil is linearly proportional to the dose. For every increase in the infusion rate by 0.1 micrograms/kg/min, the blood concentration of remifentanil increases by 2.5 ng/ml. Plasma protein binding is approximately 70%.

Remifentanil is an ester-metabolized opioid, which is metabolized by non-specific blood and tissue esterases. Remifentanil is metabolized to a carboxylic acid metabolite that has negligible activity compared to the parent compound. The half-life of this metabolite in healthy adults is 2 hours. With normal kidney function, 95% of the primary metabolite is excreted via the kidneys within 7-10 hours.

Oxycodone

The absolute bioavailability of oxycodone is 60–87% after oral administration, and maximum plasma concentrations are reached after approximately 1 to 1.5 hours.

At steady state, the distribution volume for oxycodone is 2.6 L/kg, and plasma protein binding is 38–45%.

Oxycodone is metabolized in the intestines and liver via the P450 cytochrome system to noroxycodone (CYP3A4) and oxymorphone (CYP2D6), as well as to several glucuronide conjugates. The contribution of the metabolites to the overall pharmacodynamic effect is negligible.

At steady state, the plasma elimination half-life is approximately 3 hours. Oxycodone and its metabolites are excreted via urine.

Hydromorphone

Hydromorphone is a semi-synthetic opioid that is about 5–10 times more potent than morphine. The oral bioavailability of hydromorphone is 30–35%. Peak plasma concentrations are achieved within 30–60 minutes after oral administration, with a half-life of approximately 2–3 hours.

Hydromorphone undergoes hepatic metabolism to hydromorphone-3-glucuronide, which is inactive. The majority of hydromorphone is eliminated through the kidneys, with about 90% of the dose excreted in urine within 24 hours. Only a small amount is excreted unchanged.

Hydromorphone is commonly used for managing moderate to severe pain and is available in both immediate-release and extended-release formulations for oral and parenteral use.

Methadone

Methadone is a long-acting opioid agonist with a half-life that can range from 8 to 59 hours, making it suitable for both pain management and opioid dependence treatment. Methadone has high oral bioavailability, ranging from 70% to 90%, and peak plasma concentrations are reached within 2 to 4 hours after oral administration.

Methadone is primarily metabolized in the liver by the cytochrome P450 enzyme system, particularly CYP3A4, CYP2B6, and CYP2D6, to inactive metabolites. It is eliminated primarily through the kidneys, but due to its long half-life, methadone can accumulate with repeated dosing, necessitating careful monitoring to avoid toxicity.

Methadone’s unique pharmacokinetics and NMDA receptor antagonist properties make it useful for managing neuropathic pain as well as for maintenance therapy in opioid dependence.

Codeine

Codeine is a prodrug that is converted to morphine in the liver, primarily through the action of CYP2D6. Its analgesic effects are largely due to this conversion, although codeine itself has weak opioid activity. The oral bioavailability of codeine is about 50%, and peak plasma concentrations are reached within 1 to 2 hours after oral administration.

Codeine’s half-life is approximately 3 hours. It is metabolized in the liver, and about 10% of the dose is converted to morphine. The remainder is metabolized to inactive compounds, which are excreted in the urine.

Codeine is commonly used for mild to moderate pain and is often combined with non-opioid analgesics such as acetaminophen or aspirin to enhance its efficacy. It is also used as a cough suppressant in low doses.

Tramadol

Tramadol is a centrally acting analgesic with a dual mechanism of action. It acts as a weak opioid agonist and also inhibits the reuptake of serotonin and norepinephrine, which contributes to its analgesic effects. The oral bioavailability of tramadol is approximately 70%, and peak plasma concentrations are reached within 2 hours after oral administration.

Tramadol is metabolized in the liver, primarily by CYP2D6 and CYP3A4, to an active metabolite, O-desmethyltramadol, which has a higher affinity for opioid receptors than tramadol itself. The elimination half-life of tramadol is about 6 hours, while the half-life of its active metabolite is slightly longer.

Tramadol is commonly used for moderate to moderately severe pain. Due to its dual mechanism, it has a lower potential for abuse compared to stronger opioids, but it still carries a risk of dependence and has notable side effects, including nausea, dizziness, and risk of seizures, especially at higher doses.

Buprenorphine

Buprenorphine is a partial opioid agonist that is used in the treatment of both pain and opioid dependence. It has high receptor affinity but lower intrinsic activity, which makes it effective for pain relief while reducing the risk of respiratory depression compared to full opioid agonists. The bioavailability of buprenorphine depends on the route of administration, with sublingual bioavailability around 30% and transdermal bioavailability ranging from 10% to 15%.

The half-life of buprenorphine is long, typically ranging from 24 to 37 hours, which makes it suitable for once-daily dosing in both pain management and addiction treatment. Buprenorphine is metabolized in the liver by CYP3A4 to norbuprenorphine, which is an active but less potent metabolite. Both buprenorphine and its metabolites are primarily excreted via the feces.

Buprenorphine is commonly used as a transdermal patch for chronic pain or as sublingual tablets or films for opioid substitution therapy. Its partial agonist properties make it safer than full agonists, particularly in terms of overdose risk, but it can still cause dependence.

Naloxone

Naloxone is an opioid antagonist used primarily to reverse opioid overdose. It works by competitively binding to opioid receptors without activating them, thereby reversing or blocking the effects of opioids, particularly respiratory depression. Naloxone has a very low oral bioavailability, so it is typically administered parenterally (intravenously or intramuscularly) or intranasally.

The onset of action is rapid, with effects seen within 2 to 5 minutes after intravenous injection. The half-life of naloxone is relatively short, about 1 to 1.5 hours, so repeated doses or continuous infusions may be necessary in cases of overdose involving long-acting opioids. Naloxone is metabolized in the liver and excreted in the urine.

Naloxone is also used in combination with buprenorphine in formulations designed to treat opioid dependence. In these combinations, naloxone is intended to deter misuse of the medication by injection, as it is inactive when taken orally but will precipitate withdrawal if injected.

Naltrexone

Naltrexone is an opioid antagonist used primarily in the treatment of opioid dependence and alcohol dependence. Unlike naloxone, which is used for acute opioid overdose, naltrexone is used for long-term management by blocking the euphoric and sedative effects of opioids. Oral bioavailability is about 5–40%, and peak plasma concentrations are reached within 1–2 hours after administration.

Naltrexone has a half-life of 4–13 hours, but its active metabolite, 6-beta-naltrexol, has a much longer half-life of 13–25 hours, contributing to its prolonged effects. Naltrexone is metabolized in the liver and excreted in urine, primarily as 6-beta-naltrexol.

Naltrexone is often used in combination with behavioral therapies for opioid dependence. It is also available in extended-release formulations, such as a monthly injection, to improve adherence in patients undergoing treatment for opioid or alcohol dependence.

Tapentadol

Tapentadol is a centrally acting analgesic that combines mu-opioid receptor agonism with norepinephrine reuptake inhibition, giving it a dual mechanism of action similar to tramadol, but with greater opioid activity. The oral bioavailability of tapentadol is around 32%, and peak plasma concentrations are reached in about 1.25 hours after oral administration.

Tapentadol is metabolized mainly through glucuronidation, and it is not dependent on the cytochrome P450 enzyme system for metabolism. The half-life of tapentadol is about 4 hours, and it is excreted mainly via the kidneys.

Tapentadol is used for the treatment of moderate to severe pain, both acute and chronic. Its dual mechanism of action allows for effective pain relief with potentially fewer gastrointestinal side effects compared to pure opioids.

Pethidine (Meperidine)

Pethidine, also known as meperidine, is a synthetic opioid used for the treatment of moderate to severe pain. It has a rapid onset of action, with peak plasma concentrations reached within 15 minutes after intravenous administration and within 1–2 hours after oral administration. The oral bioavailability of pethidine is low, around 50%.

Pethidine is metabolized in the liver to normeperidine, an active metabolite that can accumulate with repeated dosing and may cause neurotoxic effects, including seizures. The half-life of pethidine is 3–5 hours, but the half-life of normeperidine is much longer, up to 20 hours.

Due to its potential for neurotoxicity and its lower efficacy compared to other opioids, pethidine is now rarely used in long-term pain management. It is more commonly used in acute settings, such as labor pain or postoperative pain.

Dextropropoxyphene

Dextropropoxyphene is a weak opioid analgesic that has been used for mild to moderate pain. It has been withdrawn from the market in many countries due to concerns about its safety, particularly its association with fatal overdoses and cardiac toxicity. The oral bioavailability of dextropropoxyphene is about 40–60%, and it has a half-life of 6–12 hours.

It is metabolized in the liver to norpropoxyphene, which has a longer half-life and can accumulate with chronic use, increasing the risk of toxicity. Dextropropoxyphene and its metabolites are excreted primarily in urine.

Due to the risks associated with its use, dextropropoxyphene has largely been replaced by safer alternatives for pain management.

Conventional Pain Management

This section presents different treatments and doses for postoperative pain management. Pharmacological treatment is usually combined with different types of regional anesthesia. Below is a list of postoperative standard treatments, often combined with nerve blocks or infiltration anesthesia.

Here are some common suggestions for pain treatment:

• Paracetamol (Perfalgan®, Alvedon®, Panodil®) 1 g x 4 for adults, orally or intravenously (rectal administration is now uncommon)
• Ketobemidone (Ketogan®) 1-2.5–5 mg i.v./i.m. as needed. Normal dose 4–6 times/day. Ketogan can also be given orally 5 mg x 4. For severe pain conditions, Ketobemidone can be combined with intravenous Ketamine, 1.5 mg/ml 1-2 ml/hour (K + K)
• Morphine (morphine) 1-2-5 mg intravenously as needed. Normal dose 4–6 times/day. Usual dose: 5 mg x 3
• Oxycodone (OxyContin®) orally 10-20 mg x 2, 1-2-5 mg intravenously as needed
• Oxycodone (OxyNorm®) orally 5 mg as needed, max x 4
• Oxycodone + Naloxone (Targiniq®) 20 mg/10 mg x 2
• Morphine (Depolan®) orally 10-30 mg x 2
• Tapentadol (Palexia Depot®) 50 mg x 2 (max 500 mg/day)
• Diclofenac (Voltaren®) 50-100 mg x 2
• Tramadol (Tramadol®) 50-100 mg 1-3 times/day orally
• Etoricoxib (Arcoxia®) 60-120 mg x 1. Dose reduction for elderly patients
• Parecoxib (Dynastat®) 40 mg x 1 i v
• Ketorolac (Toradol®) 15-30 mg x 1
• Pregabalin (Lyrica®) 150 mg x 2-3

Opioids – Potency

Pharmacokinetics of Opioids

Opioids for Long-Term Non-Cancer-Related Pain

Background

Chronic pain generally refers to pain lasting more than 3-6 months. This pain is often multifactorial. For advice on non-pharmacological treatment, see the therapeutic group’s website: www.vgregion.se/lakemedel/smarta. Treatment with opioids for long-term non-cancer-related pain should always be considered a time-limited trial. When acute nociceptive pain transitions to a chronic condition, it involves changes in the central nervous system. It is essential to reassess how further treatment should be handled. Opioid trials, regardless of the substance, may be considered in selected cases where reasonable attempts at etiological and other symptomatic treatments have been made. The evidence for sustained pain-relieving effects of long-term opioid treatment is weak. Liberal prescribing of opioids to many patients increases the risk of severe side effects, including dependence development.

Before Prescribing

Before initiating opioid treatment, assess risk factors for abuse and potential future dependency, such as younger age, mental health issues, a history of substance abuse, high doses, multiple prescribers, and/or low adherence to prescribed treatment. It is also crucial to evaluate whether the patient has mental and/or physical conditions where opioids could pose health risks. Consultation with or referral to a specialist is recommended in such cases.

Pharmacological Treatment

Treatment decisions should be based on a pain analysis assessing the cause of the pain and whether opioid therapy is appropriate. Together with the patient, set functional and quality-of-life goals beyond pain relief and define what the treatment should aim to achieve. Evaluate whether there are elements of neuropathic and/or inflammatory pain that need to be treated separately, and whether adjunctive treatments, such as tricyclic antidepressants, should be considered. Also, assess whether non-pharmacological treatments could complement or even replace pharmacological therapy. Encourage the patient to try physical activity, acupuncture, TENS, and/or heat therapy. Patients often require support and knowledge to manage their lives while living with pain. For more information, see the extended therapeutic recommendations on non-pharmacological treatment on the therapeutic group’s website (see column 1).

Treatment Responsibility

When initiating opioid treatment, the prescriber holds treatment responsibility. Opioid prescriptions should be issued by a single entity and a named physician known to the patient. The patient should also be informed that prescriptions will not be issued by other providers without agreement, and that they must adhere to the prescription. The prescribing physician retains treatment responsibility until an informed colleague takes over. It is essential to plan how the treatment will proceed and schedule follow-up appointments. The patient must have access to a knowledgeable doctor who can issue prescriptions promptly to prevent withdrawal or pain breakthroughs while waiting for contact with the responsible physician. Written contracts can be used for clarity on prescription terms.

Prescribing

For all opioid prescriptions, patient consent for the prescriber to access the Medication List should be mandatory. Aim for long-acting formulations, and if short-acting opioids are considered, specify the allowed quantity. Some preparations have a maximum dose, but most “strong” opioids do not have a defined maximum dose. It is crucial to have a plan before starting treatment on what is considered a reasonable dosage. Strive for the lowest possible dose and avoid prescribing large packages. The prescribed amount should match the follow-up time, meaning that only the amount needed until the next agreed follow-up should be prescribed to reduce the risk of overdose. Consider using dispensing intervals. Avoid concurrent treatment with benzodiazepines and opioids, as this combination increases the risk of fatal intoxication.

Dosing

Start with a low dose and evaluate each increase. Keep in mind that the maximum dose of codeine is 240 mg/day (= T. Citodon 2×4), which converts to about 24-36 mg of morphine/day, but due to genetic variations and/or drug interactions, the amount of morphine obtained can vary significantly between individuals. Codeine is therefore not recommended. Also, remember that oxycodone in oral form is 1.5-2 times as potent as morphine. If a patient has tried an opioid at a dose equivalent to 60 mg of morphine/40 mg of oxycodone per day without effect, there is little chance of success with further dose increases. If there has been no effect after one month of treatment, it is also unlikely that extending the treatment will provide results. For long-term non-cancer-related pain, daily doses should rarely exceed 90 mg of morphine/60 mg of oxycodone. The potential pain relief benefit from increasing the dose beyond these amounts is small compared to the risk of developing tolerance and dependency. If higher daily doses are deemed necessary, a pain specialist should be consulted. For general advice on other opioids, see the REK list. An updated conversion table is also available on the therapeutic group’s website.

Risks

Opioids are associated with side effects that need to be monitored, as they can be harmful or, in extreme cases, lethal. Sensitivity varies greatly between individuals, and for the most sensitive, the dose can easily become too high, particularly in elderly patients. There is a risk of dosing errors when switching between different opioid preparations due to differences in equipotency and bioavailability. Long-term opioid treatment at high doses has been shown to be a risk factor for endocrine system disturbances. Symptoms such as depression, increased fatigue, decreased libido, and/or breast enlargement can be signs of endocrine disorders. Increased vigilance for signs of endocrine disturbances is recommended for patients on daily doses equivalent to 100 mg of morphine or higher and with treatment durations longer than six months.

Follow-Up

The initial follow-up of opioid treatment should occur within 1-4 weeks, and subsequently every three months, to assess whether to continue the dosage or discontinue the treatment. During follow-up visits, evaluate with the patient which functional or quality-of-life parameter has been achieved. Pain questionnaires like the BPI (Brief Pain Inventory) or PDI (Pain Disability Index) can serve as a basis for such discussions. The evaluation should balance the treatment’s effectiveness with its side effects, and the patient must be actively involved in assessing the treatment results. During the course of treatment, adherence to the prescription should also be evaluated, and low adherence could be a reason to discontinue further prescribing.

Tapering and Discontinuation

The following recommendations for opioid tapering do not apply to patients with underlying psychiatric illness and/or substance abuse, who require care within specialist psychiatry. The prescribing physician is responsible for initiating and conducting the tapering process, with advice from other specialists if necessary. When taking over a patient from another level of care, the responsibility for tapering and discontinuing treatment is also assumed. Before initiating opioid tapering, it is important to determine whether a dependency disorder is present. The diagnosis of medication dependence is based on the presence of a behavioral disorder. Without behavioral disturbances, dependence cannot be assumed. Behavioral disturbances can manifest as claims of lost medication, early prescription refills, unauthorized dose increases, erratic behavior concerning medications, and multiple prescribers unaware of each other. Tolerance and withdrawal symptoms are common in dependency disorders but can also occur without dependence. Tapering should be done in percentage reductions rather than fixed milligram steps, as withdrawal symptoms can vary between individuals. It is easier to reduce the dose at the beginning of the tapering process. Tapering should be viewed as a one-way process – never return to a previously higher dose. If the patient finds the reduction difficult, maintain the current dose for a little longer than planned. Opioid withdrawal is rarely dangerous but is often perceived as highly distressing. Untreated opioid withdrawal usually lasts a few weeks, with the most symptoms occurring during the first week. Withdrawal symptoms such as nausea, diarrhea, muscle pain, and myoclonus can be alleviated with clonidine 0.1–0.2 mg orally every six hours (T. Catapresan 75 ug, licensed drug).

Tapering without Dependence

The patient usually wants to be free of opioids, and the key is to find the right pace for tapering. This process can take anywhere from a few weeks to several months, depending on individual differences, the duration of opioid treatment, and the doses involved. The important thing is that tapering continues in the right direction. After long-term opioid treatment, a reduction rate of approximately 5-10% per week from the initial dose is often feasible, with a slower pace at the end. Short-term postoperative opioid treatment should be tapered off over a few weeks if the process goes smoothly.

Tapering with Dependence

In this case, the prescriber must take firm control of the tapering process, as the patient is often ambivalent at best and completely resistant at worst. Fixed, clear schedules must be followed, regardless of the patient’s potential outbursts. In chaotic situations, tapering should be completed within 3-4 weeks, with each date corresponding to a specific dose. If the patient, despite their dependence, is cooperative and the situation is more stable, the tapering can take significantly longer. Tapering should not be tied to the expectation of finding “alternative pain relief” that is as effective, as this will likely never be found in such a situation. When the patient is required to reduce their dosage of the substance to which they are addicted, it will trigger strong reactions, regardless of who initiates the process. Specialist knowledge is not necessarily required in this situation, but consultations with specialists can be sought if needed for further guidance. Non-pharmacological and/or non-opioid treatments can be tried, but if they do not provide the desired effect, this is not a reason to stop the tapering process. For further advice on tapering and discontinuation, see FAS UT 3 (www.fasut.nu).

Level of Care

Opioids for long-term non-cancer-related pain can be initiated and discontinued in both inpatient and outpatient care. In cases of complicating psychiatric and/or somatic illnesses, specialists may need to be consulted.

References

1. The Swedish Medical Products Agency’s recommendations. Use of opioids in non-cancer-related pain. 2002.
2. CDC Guideline for Prescribing Opioids for Chronic Pain – United States 2016. JAMA. 2016;315(15):1624-1645.
3. Watson CPN. Chronic non-cancer pain and the long-term efficacy and safety of opioids: Some blind men and an elephant? Scand J Pain 2012;3:5-13.
4. Sullivan MD et al. Problems and concerns of patients receiving chronic opioid therapy for chronic non-cancer pain. Pain 2010; 149: 345-53.
5. Kissin I. Long-term opioid treatment of chronic nonmalignant pain: unproven efficacy and neglected safety? J Pain Res 2013; 4: 513-29.
6. Lundgren Claes. FAS UT 3.

Titration Scheme for Subcutaneous Morphine Pump with PCA

Initiate treatment according to the starting dose. Evaluate the effect by assessing pain scores and requested/received PCA doses daily to adjust the dose as indicated below. Also assess any side effects.

If more than 3-4 bolus doses per day are required, consider increasing to the next step. If the effect of bolus doses is insufficient (which can be suspected if more doses are requested than delivered, i.e., the patient presses again within the lockout time), but there are long periods of pain relief, the base dose can be maintained, and only the PCA dose increased by 25% to achieve the desired effect.

– If only one bolus dose per day or fewer is used and/or side effects occur, consider reducing the dose to the previous step.

Medication: Morphine 5 mg/ml, in a 50 ml cassette

Starting Dose:

Step 1: Continuous infusion 0.1 ml/h = 12 mg/day

PCA dose 0.4 ml = 2 mg

Lockout time 30 minutes / 2 boluses per hour – same in all steps unless otherwise prescribed by a physician experienced in pain management.

Step 2:

Continuous infusion 0.2 ml/h = 24 mg/day

PCA dose 0.8 ml = 4 mg

Step 3:

Continuous infusion 0.3 ml/h = 36 mg/day

PCA dose 1.2 ml = 6 mg

If the effect is insufficient at step 3, switch to a cassette with 10 mg/ml.

Step 4: Morphine 10 mg/ml, 50 ml cassette

Continuous infusion 0.2 ml/h = 48 mg/day

PCA dose 0.8 ml = 8 mg

Continue to increase by 0.1-0.2 ml per hour as needed. PCA dose should be 1/6th of the daily dose.

Ketamine in Pain Management

Ketamine/Ketanest (Esketamine) in Low Doses for Pain

Ketamine (S and R, see below), which is an NMDA receptor blocker, modulates both surgically induced and drug-induced hyperalgesia at doses significantly lower than those required for general anesthesia. (Hyperalgesia = increased response to painful stimulation.) Ketamine has an opioid-sparing effect.

There are two isomers: Ketamine-S and Ketamine-R

• Ketanest = Ketamine-S = Esketamine. Ketanest is about twice as potent as Ketalar and causes less cognitive impairment.
• Ketalar = Ketamine in racemic form (50% Ketamine-R + 50% Ketamine-S).

Indications

• Expected postoperative pain issues
• Amputation (upper, lower extremity)
• Acute phantom pain
• Patients with chronic pain + acute pain
• Ongoing high opioid medication (opioid-tolerant patient) + acute pain
• History of substance abuse (when avoiding opioids) + acute pain

Dosage

Perioperative Ketanest infusion; low-dose infusion (as an adjunct to local, regional, or general anesthesia)

• At start of surgery: 0.1 – 0.3 mg/kg bolus IV
• Maintenance dose: 0.1 – 0.3 mg/kg/h IV
• After the last suture is placed: 0.03 mg/kg/h IV
• Postoperative for 12 – 72 hours: 0.03 – 0.06 mg/kg/h intravenously.

Postoperative Ketanest or Ketanest for Non-Operated Patients

• Single bolus doses: 0.1 mg/kg IV
• And/or low-dose infusion:
  • Loading dose (bolus): 0.1 mg/kg IV
  • Maintenance dose: 0.03 – 0.06 mg/kg/h IV, administered over 12 – 72 hours.

Medication Combinations and Recommendations

• Ketanest is often combined with low-dose midazolam or another benzodiazepine.
• Increased salivation is common with Ketanest treatment; administer Glycopyrronium (Robinul) or Atropine IV.
• No significant interactions are known when Ketanest is given at low doses, so other prescribed analgesics (paracetamol, NSAIDs, COX-2 inhibitors, opioids, clonidine, gabapentin, pregabalin, local anesthetics) should be continued.
• Ketanest should not be mixed with morphine in the same IV-PCA pump.
• Ketanest is not recommended for IV-PCA use.
• The seizure threshold may be lowered when combined with xanthine derivatives (e.g., Aminophylline and Theophylline), so these combinations should be avoided.
• The drug should not be used together with Ergometrine (Ergotamine).

Monitoring and Documentation

• Patients receiving low-dose Ketanest infusion IV are typically monitored in Post-op/ICU.
• Document sedation level, NRS/VAS, respiratory rate, SaO2, pulse, and blood pressure.
• Actively inquire about nightmares, hallucinations, and visual disturbances during checks.

Side Effects

• Nightmares, hallucinations, or visual disturbances appear to be insignificant with low-dose infusion and/or single boluses. Administer 1 – 3 mg Midazolam IV (or another benzodiazepine) if needed.
• Increased salivation. Administer Robinul (Glycopyrronium) or Atropine IV.

Contraindications

• Hypersensitivity to the active substance or any of the excipients.
• Eclampsia and pre-eclampsia.
• Patients at significant risk from increased intracranial pressure.
• Patients at significant risk from increased blood pressure.

Warnings and Precautions

• Tachyarrhythmias
• Untreated hypertension
• Increased cerebrospinal pressure, head injury, or hydrocephalus
• Increased intraocular pressure (e.g., glaucoma) or eye injury
• Alcohol intoxication
• History of psychiatric illness (e.g., schizophrenia and acute psychosis)
• Hyperthyroidism
• Acute intermittent porphyria

References

1. FASS 2017
2. Christensen KF, Brandsborg B, Nikolajsen L: Perioperative ketamine for the treatment of acute postoperative pain. Expert Opinion. J of Sympt and Signs, 2013;2:398-402

Epidural Anesthesia (EDA) in Pain Management

Epidural Opiates

The registered medications for epidural use in Sweden are Morfin Special (morphine) and Sufenta (sufentanil). Fentanyl (Fentanyl) is also used epidurally. The medications are administered continuously via infusion or intermittently in bolus doses, 3-4 times per day. Morphine can be given three times per day or in continuous infusion.

Dosage:

• Morphine 3-4 mg x 3 in EDA. Initially, up to 5 mg morphine hydrochloride can be given if needed. If necessary, a dose of 2-4 mg morphine hydrochloride can be administered when the effect of the first dose has waned, which typically occurs after 6-24 hours.
• Fentanyl 2 μg/ml, 4-12 ml/hour in continuous infusion with or without a local anesthetic.
• Sufenta 1 μg/ml, 8-16 ml/hour in continuous infusion with or without a local anesthetic. Sufenta can also be administered in bolus doses without a local anesthetic, 25 μg epidurally x 3-4 times per day.

EDA Patient Monitoring

• Pulse and blood pressure every 4 hours
• Pain intensity (VAS) every 4 hours
• Motor function in arms and legs (according to Bromage) every 4 hours
• Insertion site checked once per shift
• Respiratory rate every 4 hours when opioids are added
• Sedation level every 4 hours when opioids are added.

The above checks can be performed every 6 hours after 24 hours without dose increase. Additional checks 10 and 30 minutes after increased infusion rate or epidural bolus dose. Additional checks 30 and 60 minutes after reactivation of EDA. Extra checks 2 times per hour for 2 hours when adding sedative or respiratory-depressing medications. Dose increases and bolus doses are given only after consultation with a pain nurse or anesthesiologist. Infusion sets should be changed every 3 days.

EDA and Anticoagulants

There should be at least 10 hours between LMWH administration (Klexane or Fragmin) and EDA placement or adjustment of catheter position.

The EDA should be removed > 2 hours before or > 10 hours after LMWH administration. Monitor motor function (Bromage) 6, 8, and 12 hours after removing the epidural catheter. Document the findings! The urinary catheter should remain in place for 6 hours after removing the epidural catheter.

EDA Complications

An epidural hematoma is a rare but serious complication that requires immediate attention. Symptoms include back pain and sometimes radiating pain into the legs, as well as progressive leg paralysis. An epidural abscess is another serious complication that requires immediate attention. Symptoms include fever, general malaise, back pain, and progressive leg paralysis.

If any of these complications are suspected, the EDA infusion should be stopped immediately, and an anesthesiologist should be contacted!

Motor Function According to Bromage

0: Full mobility in the hip, knee, and foot
1: Can move the knee and hip, but cannot lift the leg
2: Can move the ankle
3: Cannot move the knee or ankle

Motor Function in Arms

0: Normal motor function in the arms
1: Weakness in the arms

Sedation Level

0: Fully awake
1: Drowsy, slightly sedated
2: Sedated but arousable
3: Deeply sedated, unarousable
S: Sleeping naturally

Nausea

0: No nausea
1: Untreated nausea
2: Treated nausea
3: Vomiting

Itching

0: No itching
1: Untreated itching
2: Treated itching

Patient-Controlled Analgesia (PCA)

Self-Administered Parenteral Pain Management

This refers to continuous or intermittent infusion of pain relief with the option for the patient to self-administer extra doses as needed (bolus doses). PCA can be administered intravenously, subcutaneously, or epidurally. Common pumps used include GEM-star, CAD, or Deltec. The method allows for relatively stable plasma concentrations of administered drugs, enabling the patient to manage the treatment based on activities and pain relief needs. This method compensates for the large inter-individual differences in postoperative pain relief requirements. Typically, PCA is used for 2-4 days following moderate to major surgical procedures. Risk groups include elderly patients, severely overweight patients, patients with respiratory insufficiency, severely debilitated or confused patients, and patients with a history of substance abuse.

Standard PCA Infusion

Morphine 1 mg/ml, 1-2 ml, 1-2 mg in bolus with a lockout time of 6-10 minutes. A common setting is 1 ml (1 mg) per bolus with a lockout time of 6 minutes, allowing a maximum dose of 10 mg/hour and 10 ml. A lockout volume after 4 hours is 40 ml if requested by the pump. Ketogan 1 mg/ml and Ketamine can also be used.

The goal with PCA is a VAS score < 4 and 1-2 bolus doses per hour. On the ward, it is important to monitor and check VAS, respiratory rate, sedation level, nausea, itching, and bladder function every four hours. Extra checks should be performed if doses are increased, with checks every 30 minutes for two hours. In case of insufficient pain relief, loading doses can be given every 10 minutes until adequate relief is achieved. Consider increasing bolus doses by 25-50%. If the number of PCA doses exceeds 3 per hour, the bolus dose should be increased. If the number of desired doses exceeds the number actually administered, the bolus dose should be increased. Consider adjunctive pain therapy.

Monitoring During PCA and Intravenous Opioid Treatment:

Every 4 hours, check the following:

• VAS (pain scale)
• Sedation level
• Respiratory rate
• Nausea
• Itching

Bladder function should be checked every 8 hours.

If the patient does not have a urinary catheter, check residual urine once per day.

Extra checks should be done 30 minutes after dose increases or the addition of sedating or respiratory-depressing medications.

Infusion sets should be changed every 3 days.

Patient-Controlled Epidural Anesthesia (PCEA)

Self-Administered Epidural Pain Management

This involves a continuous infusion plus patient-controlled bolus doses or intermittent infusion with only bolus doses, administered epidurally, allowing the patient to control the treatment as needed by administering small bolus doses. PCEA is administered epidurally, and the goal is to provide better pain relief with lower total doses compared to continuous infusion. This method allows the patient to adjust the treatment according to their activities and pain relief needs. It compensates for the large inter-individual differences in postoperative pain relief requirements. Typically, PCEA is used for 2-4 days following moderate to major surgical procedures and during labor analgesia. PCEA is particularly suited for labor analgesia and has been shown to provide better pain relief compared to conventional epidural anesthesia. For labor analgesia, PCEA can be administered either as patient-administered bolus doses only or as continuous infusion plus PCEA. When using only bolus doses, larger doses are given compared to the combination of continuous infusion with PCEA, for example, 5 ml instead of 2 ml per dose.

Risk groups include elderly patients, severely overweight patients, patients with respiratory insufficiency, severely debilitated or confused patients. For labor epidural anesthesia, the main risk groups are severely overweight patients and those with preeclampsia.

Common pumps used include GEM-star, CADD, or Deltec.

Standard PCEA Infusion

Continuous infusion of 4-10 ml/hour. Bolus dose 2 ml, with a lockout time of 10 minutes and a maximum number of bolus doses per hour set to 4. With a maximum infusion rate of 10 ml/hour and a maximum of 4 bolus doses, the total allowable dose is 18 ml/hour, calculated as the highest permissible dose.

Some Suggestions for Combination Treatment with PCEA:

• Marcain (bupivacaine) 1.0 mg/ml + Fentanyl 2 μg/ml + Adrenaline 2 μg/ml. Dosage: 4-10 ml/hour, bolus dose 2 ml.
• Narop (ropivacaine) 2 mg/ml, + Sufenta 1 μg/ml, 3-10 ml/hour, bolus 2 ml during the surgery day. The next morning, you can switch to Narop 1 mg/ml + Sufenta 0.5 μg/ml to allow for patient mobilization as prescribed by the surgeon. This infusion can continue for a few more days.

Strength

Solution: 50 μg/ml. This is approximately 100 times more potent than morphine (1 ml fentanyl ≈ 5 mg morphine).

Concentration

Fentanyl is administered in a 50 μg/ml concentration, often used in anesthesia procedures for its potent opioid effects, being 100 times stronger than morphine when dosed in similar volumes. Proper monitoring and dosage adjustment are essential due to its high potency and rapid onset of action.

Proposal for Delivery Epidural (EDA) with PCEA

• Marcain (bupivacaine) 0.6 mg/ml + Sufenta 0.5 μg/ml, continuous infusion of 5 ml/hour, bolus 5 ml. Lockout time 30 minutes.

During treatment in postop/ICU/delivery unit, the number of requested bolus doses, delivered doses, and total administered dose should be recorded and documented. The goal of PCEA is VAS < 4 and 1-2 bolus doses per hour. On the ward, it is important to perform checks every four hours of VAS, respiratory rate, sedation level, nausea, itching, and bladder function. Additional checks should be done if doses are increased, with monitoring every 30 minutes for two hours. In case of insufficient pain relief, loading doses can be given every 10 minutes until satisfactory pain relief is achieved. If the number of PCEA doses exceeds 3 per hour, increase the continuous infusion. If insufficient pain relief is observed at the maximum dose, consider adjuvant pain treatment or epidural adjustment.

In patients with mild preeclampsia, coagulation tests should be checked no later than 6 hours before the epidural is placed. In severe eclampsia, these tests (PT/APTT/platelets) should be no older than 2 hours.

Intrathecal Pain Treatment

Intrathecal Pain Treatment for Advanced Pain

Intrathecal pain treatment is performed by inserting an epidural catheter under strict sterile conditions into the spinal space via lumbar puncture using an epidural needle. The catheter is then used for continuous spinal anesthesia via a pump – e.g., Gemstarpump or CAD-pump. This puncture is performed similarly to spinal anesthesia using an epidural needle. Through the epidural needle, the spinal space is first identified with a spinal needle, using the “needle-through-needle” technique. The epidural catheter is then inserted high, approximately 15 cm after insertion at L2-L3. The catheter can advantageously be tunneled subcutaneously from the insertion site to the patient’s side. Intrathecally administered medication is 100–300 times stronger than orally administered medication.

Contraindications: elevated intracranial pressure, sepsis, severe coagulation disorder, increased bleeding risk, anticoagulation therapy (Warfarin, Plavix), and infected skin, e.g., pressure sores near the insertion area.

Preoperative blood tests:
PT(INR), APTT, platelets, CRP.

Anticoagulation-Treated Patients

Warfarin treatment is discontinued – the operating physician will communicate the acceptable INR in each case. Patients treated with low-molecular-weight heparin, such as Fragmin, should be managed as follows: After Fragmin 5000 IU s.c., wait 10 hours before insertion, adjustment, or removal. The next Fragmin dose is administered 2 hours after insertion or removal of the intrathecal catheter.

For Clexane 40 mg s.c., wait 10 hours before insertion, adjustment, or removal. The next Clexane dose is administered 2 hours after insertion, adjustment, or removal of the intrathecal catheter. Plavix is discontinued 10 days before the procedure.

Medications for Intrathecal Administration

95 ml of Marcain 5 mg/ml is mixed with 5 ml of Morphine 10 mg/ml to a total volume of 100 ml. The concentration of Marcain (bupivacaine) becomes 4.75 mg/ml, and the concentration of morphine becomes 0.5 mg/ml. A recommended starting dose is 0.3 ml/hour, with the option to administer a bolus dose of 0.2 ml if needed.

Perioperative pain relief is usually achieved by administering local anesthetics with added opioids, typically morphine 0.1 mg, 100 μg.

There is an option to administer a mixture of opioids and clonidine (Catapresan). An example of such a mixture is:

• Morphine Special 0.1-0.3 mg, 0.4 mg/ml, 0.25–0.75 ml
• Sufenta (sufentanil) 10 μg, 5 μg/ml, 2 ml
• Catapresan (clonidine) 75 μg, 150 μg/ml, 0.5 ml

Monitoring for Intrathecal (Subarachnoid) Opioid Administration

After morphine has been administered intrathecally, the following monitoring should be performed for 12 hours, and after intrathecal fentanyl or sufentanil has been administered, monitoring should continue for 6 hours.

Once per hour after spinal anesthesia is administered, the following should be checked:

• VAS
• Sedation level
• Respiratory rate (if sedation level >1)
• Nausea
• Itching

Thereafter, monitoring should be performed as above every 4 hours for an additional 12 hours.

Extra monitoring should be done 2 times/hour for 2 hours when sedative or respiratory-depressing medications are added.

Urinary catheterization for at least 12 hours. Check bladder function after catheter removal.

Fentanyl

Fentanyl is a potent opioid and a short-acting intravenous anesthetic and analgesic. It is intended for use during anesthesia for surgical procedures and for sedation during painful or stressful medical interventions. Fentanyl is a selective and potent μ-opioid agonist with rapid onset and short duration of action. Despite its rapid effect, the maximum analgesic and respiratory depressive effects are reached only after a few minutes. Normally, the analgesic effect of an intravenous injection of 100 micrograms of fentanyl lasts about 30 minutes. Pharmacodynamically, fentanyl resembles morphine but is more potent in both analgesic and respiratory-depressant effects. Even in large bolus doses, fentanyl has often been used for induction of anesthesia in cardiac patients due to its cardiovascular stability and its ability to blunt hemodynamic responses to intubation.

Plasma protein binding is 80-85%. Fentanyl is not bound to plasma cells, and its protein binding is minimally affected by pH. Fentanyl is metabolized in the liver to inactive metabolites.

Plasma concentrations of fentanyl decrease rapidly after an intravenous injection. Fentanyl’s elimination is triphasic, with half-lives of approximately 1 minute, 15 minutes, and 6 hours. The distribution volume in the central compartment is approximately 15 liters, and the total distribution volume is approximately 400 liters. Secondary peaks in plasma levels can occur. Approximately 75% of the dose is eliminated within 72 hours.

Dosing

In anesthetic procedures, the usual initial dose of fentanyl for adults is 50-100-200 μg, 1-2-4 ml, administered slowly intravenously. The dose can be repeated 20-30-45 minutes after the initial dose. Secondary respiratory depression has been observed in cases where large doses have accumulated. With continuous infusion, there is a risk of accumulation.

Fentanyl should be used with caution in patients with uncompensated hypothyroidism, lung disease, especially with decreased lung capacity, alcohol abuse, liver or kidney insufficiency. Tolerance and dependence can be induced. Fentanyl reduces the need for hypnotics required to maintain anesthesia, so the dose of hypnotic or volatile anesthetics should be reduced.

• Intubation dose for general anesthesia: 1–8 μg/kg i.v. (70 kg = 70-600 μg = 2-12 ml).
• For children aged 2 – 12 years, 1-3 μg/kg is administered in combination with inhalation anesthesia.

TIVA Dose

Fentanyl can be given as an infusion.

• Maintenance dose for surgical anesthesia: 0.1-0.70 μg/kg/min.
• Standard dose: 0.15 μg/kg/min.
• Intubation dose: 1-2 μg/kg.

Maintenance Dose for Sedation in ICU

• Adults 0.5-2 μg/kg/hour
• Children: 0.5-1 μg/kg/hour
• Standard dose: 0.5 μg/kg/hour

In ventilated patients, a loading dose of fentanyl can be given as a rapid infusion of approximately 1 μg/kg/minute for the first 10 minutes, followed by an infusion of approximately 0.5 μg/kg/hour. Alternatively, the fentanyl loading dose can be administered as a bolus. The infusion rate should be titrated according to individual patient response; lower infusion rates may be sufficient.

In ventilated patients, a loading dose of fentanyl can be given as a rapid infusion of approximately 1 μg/kg/minute for the first 10 minutes, followed by an infusion of approximately 0.1 μg/kg/minute. Alternatively, the fentanyl loading dose can be administered as a bolus. The infusion rate should be titrated according to individual patient response; lower infusion rates may be sufficient.

TCI Dose (Insufficient Data)

Fentanyl is typically not administered in TCI mode but rather in TIVA mode or intermittently as boluses. The target maintenance concentration (TCI) for surgical anesthesia is unknown: (1-4 ng/ml?). The standard concentration is unknown (2 ng/ml?) (Cpt).

Induction: 100 μg (2 ml) administered over 10 seconds.

Concentration

Solution 50 μg/ml. – approximately 100 times the potency of morphine (1 ml fentanyl ≈ 5 mg morphine)

Strength

Approximately 100 times the strength of morphine. (1 ml fentanyl ~ 10 mg morphine).

Pharmacokinetics

The plasma concentration of fentanyl rapidly decreases after an intravenous injection. Fentanyl’s elimination is triphasic, with half-lives of approximately 1 minute, 15 minutes, and 6 hours. The distribution volume in the central compartment is around 15 liters, and the total distribution volume is approximately 400 liters. Secondary plasma concentration peaks may occur.

Fentanyl is bound to plasma proteins by approximately 80–85%. Fentanyl is rapidly metabolized, primarily in the liver via CYP3A4, mainly through oxidative N-dealkylation. Clearance is approximately 0.5 l/hour/kg. Around 75% of the dose is eliminated within 72 hours, with about 10% excreted unchanged. The half-lives may be prolonged, especially in the elderly or after repeated dosing.

Fentanyl Transdermal

After the first application of the patch, the serum concentration of fentanyl rises gradually. It typically levels off after 12–24 hours and remains relatively constant for the rest of the 72-hour application period. Steady-state serum concentration is reached by the end of the second 72-hour application, and this is maintained during subsequent applications of the same-size transdermal patch. Due to accumulation, the AUC and Cmax during a dosage interval at steady state are about 40% higher than after a single application. High interindividual variability in plasma concentrations has been observed.

Side Effects

Can cause respiratory failure and respiratory depression. It may lead to muscle stiffness, especially at high doses, and difficulties in manually ventilating the patient. It can cause drowsiness and increased fatigue. Bradycardia and hypotension can occur. Increased muscle rigidity has been observed with high doses and rapid administration. Bradycardia and possibly asystole may occur if the patient receives insufficient anticholinergics or fentanyl is combined with non-vagolytic muscle relaxants. Secondary respiratory depression has been observed.

Warning

Fentanyl reduces the need for hypnotics (inhalation anesthetics) required to maintain anesthesia, so the dose of other anesthetics should be reduced. Since the adverse hemodynamic effects of fentanyl are more pronounced and frequent in ASA IV patients compared to longer-acting opioids, great caution should be exercised when administering fentanyl to this patient population.

Esketamine (Ketanest)

Ketanest (Esketamine) in Low Dose for Pain

The S-isomer of ketamine. Ketamine (S and R, see below), a NMDA receptor blocker, modulates both surgically induced and drug-induced hyperalgesia at doses significantly lower than those required for general anesthesia. (Hyperalgesia = increased response to painful stimuli.) Ketamine has an opioid-sparing effect.

There are two isomers: Ketamine-S and Ketamine-R

• Ketanest = Ketamine-S = Esketamine. Ketanest is about twice as potent as Ketalar and causes less cognitive impact.
• Ketalar = Ketamine in racemic form (50% Ketamine-R + 50% Ketamine-S).

Indications

• Expected postoperative pain issues
• Amputation (upper, lower limb)
• Acute phantom pain
• Patients with chronic pain + acute pain
• Ongoing high opioid medication (opioid-tolerant patient) + acute pain
• History of substance abuse (when you want to avoid opioids) + acute pain

Dosing

Perioperative Ketanest infusion; low-dose infusion (as an adjunct to local, regional, or general anesthesia)

• At the start of surgery: 0.1 – 0.3 mg/kg bolus iv
• Maintenance dose: 0.1 – 0.3 mg/kg/h iv
• After the last suture is placed: 0.03 mg/kg/h iv
• Postoperative infusion for 12 – 72 hours: 0.03 – 0.06 mg/kg/h intravenously.

Postoperative Ketanest Use or for Non-Operated Patients

• Single bolus doses: 0.1 mg/kg iv
• And/or low-dose infusion:
  • Loading dose (bolus dose): 0.1 mg/kg iv
  • Maintenance dose: 0.03 – 0.06 mg/kg/h iv, administered for 12 – 72 hours.

Medication Combinations and Recommendations

• Ketanest is often combined with low-dose midazolam or another benzodiazepine.
• Increased salivation is common during Ketanest treatment; – therefore, administer Glycopyrronium (Robinul) or Atropine iv.
• No significant interactions occur when Ketanest is given in low doses, meaning that other prescribed analgesics (paracetamol, NSAIDs, Cox-2 inhibitors, opioids, clonidine, gabapentin, pregabalin, local anesthetics) should be administered.
• Ketanest should not be mixed with morphine in the same iv-PCA pump.
• Ketanest is not recommended for iv-PCA use.
• The seizure threshold may be lowered when combined with xanthine derivatives (e.g., aminophylline and theophylline), so these combinations should be avoided.
• The medication should not be used together with Ergometrine (Ergotamine).

Monitoring and Documentation

• Patients receiving iv low-dose Ketanest infusion are generally monitored in Postop/ICU.
• Document sedation level, NRS/VAS, respiratory rate, SaO2, pulse, and blood pressure.
• Actively inquire about nightmares, hallucinations, and vision disturbances during check-ups.

Side Effects

• Nightmares, hallucinations, or vision disturbances seem negligible with low-dose infusion and/or single bolus. Administer 1 – 3 mg midazolam iv (or another benzodiazepine) if needed.
• Increased salivation. Administer Robinul (Glycopyrronium) or Atropine iv.

Contraindications

• Hypersensitivity to the active substance or any excipient.
• Eclampsia and preeclampsia.
• Patients for whom an increase in intracranial pressure poses a serious risk.
• Patients for whom an increase in blood pressure poses a serious risk.

Warnings and Precautions

• Tachyarrhythmias
• Untreated hypertension
• Elevated cerebrospinal pressure, skull injury, or hydrocephalus
• Elevated intraocular pressure (e.g., glaucoma) or eye globe injury
• Alcohol intoxication
• Psychiatric history (e.g., schizophrenia and acute psychosis)
• Hyperthyroidism
• Acute intermittent porphyria

References

1. FASS 2017
2. Christensen KF, Brandsborg B, Nikolajsen L: Perioperative ketamine for the treatment of acute postoperative pain. Expert Opinion. J of Sympt and Signs, 2013;2:398-402
3. McCormick Z, Chang-Chien G, Marshall B, Huang M, Harden RN: Phantom limb pain: a systematic neuroanatomical-based review of pharmacologic treatment. Pain Medicine 2014;15:292-305
4. De Kock MF, Lavand’homme PM: The clinical role of NMDA receptor antagonists for the treatment of postoperative pain. Best Pract Research Clin Anaesthesiol, 2007;21(1):85-98
5. Suzuki M: Role of N-methyl-d-aspartate receptor antagonists in postoperative pain management. Current Opinion in Anaesthesiol, 2009;22(5):618-22
6. Hocking G, Visser EJ, Schug SA, Cousins MJ. Ketamine: Does Life Begin at 40? Pain: Clin Updates 2007;XV(3):1-6
7. Bell RF, Dahl JB, Moore RA, Kalso E: Peri-operative ketamine for acute post-operative pain: a quantitative and qualitative systematic review. Acta Anaesthesiol Scand, 2005; 49:1405-28
8. Loftus RW, Yeager MP, Clark JA, Brown JR, Abdu WA, Sengupta DK, Beach ML. Intraoperative ketamine reduces perioperative opiate consumption in opiate-dependent patients with chronic back pain undergoing back surgery. Anesthesiol, 2010;113:639-46
9. Hadi BA, Al Ramadani R, Daas R, Naylor I, Zelkó R: Remifentanil in combination with ketamine versus remifentanil in spinal fusion surgery – a double blind study. Int J Clin Pharmacol Ther. 2010;48(8):542-8
10. Hang LH, Shao DH, Gu YP: The ED50 and ED95 of ketamine for prevention of postoperative hyperalgesia after remifentanil-based anaesthesia in patients undergoing laparoscopic cholecystectomy. Swiss Med Weekly, 2011;141:w13195
11. Sveticic G, Farzanegan F, Zmoos P, Zmoos S, Eichenberger U, Curatolo M: Is the combination of morphine with ketamine better than morphine alone for postoperative intravenous patient-controlled analgesia? Anaesth Analg, 2008;106(1):287-93

Morphine and Other Strong Analgesics for Children

Peripheral Analgesics

• Ketorolac (Toradol^®) 0.3 mg/kg x 4 iv (not for < 3-6 months, COX 1+2)
• Parecoxib (Dynastat^®) 0.5 mg/kg x 1 iv (not for < 3-6 months COX 2)
• Ibuprofen 7.5 mg/kg x 3-4 po (not for < 3 months COX 1+2)
• Paracetamol po 15 mg/kg x 4 (for the first 3 days 20-25 mg/kg x 4)
• Paracetamol iv 15 mg/kg x 4 (use iv especially for the first postoperative day)

Pharmaceutical Product Information for Children