Pain and Analgesia

Pain and Treatment of Pain

Evaluating, investigating and treating our patients’ experience of pain is a fundamental part of all anesthesiological work. Expected pain should always be valued in perioperative work prior to surgical procedures and in many cases the pain constitutes the central medical problem, both before and after surgery. Patients with preoperatively known pain problems often constitute a major postoperative pain problem than usual and may need a special preoperative planning. Many times these patients require longer time on a post-operative device than usual, which is best, planned in advance.

The pain is transmitted through nociceptive or neurogenic pain courses, in addition to psychological and psychosocial factors that affect the perception of pain. The pain experience is always subjective. The pain experience varies with personality traits and the degree of basic pain sensitivity. It is generally worsened by depression, nervosity, fear and anxiety. The pain can be acute, subacute or chronic or a combination of these. Chronic pain often causes greatly impaired quality of life. Complicated pain management is best managed by cross-professional teams specializing in pain. This guide, gives you a simplified version of pharmacological treatment of pain with or without regional blockades, such as epidural anesthesia or intrathecal anesthesia. Knowledge and familiarity with different opioids is based on basic anesthesiological competence. In general, pharmacological therapy with drugs is administered by oral, intravenous, intramuscular, subcutaneous or regional via catheter retention. In these catheters, usually, but not always, a combination of local anesthetics and an opioid is given in continuous infusion. This guide mainly concerns pharmacological treatment of adults, for the treatment of children, refer to special literature. Here you will find a guide for conventional pain management, equivalents for different periods, basal pharmacokinetics, various prescriptions for pain management, oral, epidural, intrathecal and patient controlled therapy (PCA). Peroperatively, opioids are usually administered intravenously, local anesthesia is given in laparoscopic gates alternatively in the wound edges and regional blockades are added as appropriate.

In the treatment of complicated pain, a pain analysis must always be the basis for treatment. The pain analysis includes a degree of pain, for this purpose there are several different scales, for example the VAS scale. In addition, an assessment of the patient’s quality of life and mental status is made. The nociceptive pain can be divided into somatic and visceral pain. Somatic nociceptive pain comes primarily from skin, subcutaneous tissue, muscles and skeletal disorders. The visceral pain comes mainly from internal abdominal organs, intrathoracal organs, pleura or peritoneum. Neurogenic pain comes mainly from peripheral nerves, spinal cord or tumor growth in the nerve tissue. This pain is often inflammatory. The pain should be judged whether it is well-calibrated, diffuse or radiant. Nociceptive pain can often be described as, for example, molande, doving, aching, bulging, pressing, chopping or cutting. Visceral nociceptive pain is often described as cramped or pressing. Neurogenic pain can be described as burning, tingling, tingling, itchy, cramped or radiant.

Acute painChronic pain
Intact nervous pain fibersInjured nervous pain fibers
Drugs work wellModerate effect of drugs
Opiates are used in severe painOpiates are to be stepped out
Combine with non-pharmacological methodsNon-pharmacological methods are the basic treatment
Paracetamol and NSAID should be basic therapyCombine with drugs against neurogenic pain

Musculoskeletal pain is usually nociceptive somatic with an inflammatory feature. This pain is suitable for treatment with basal analgesics plus NSAIDs, steroids or opioids. ASA is unsuitable for bleeding problems or gastritis. In some cases, regional anesthesia, immunosuppression or other adjuvant treatment such as radiotherapy, radiotherapy, physiotherapy, TNS, immobilizing bandages (orthosis/gypsum) or orthopedic surgery are used. Physical exercise often has a good effect on chronic benign pain.

Pain from the viscera can be experienced as mumbling, pressing and very difficult, often with a “refer pain” feature with radiation to the right shoulder (liver) or left shoulder or back (pancreas, spleen, ventricle). Treatment may be appropriate with opioids, regional blockades (epidural anesthesia) or NSAIDs, in severe cases, intrathecal catheter with a mixture of periods and local anesthetic agents. Avoid NSAIDs in gastritis / ulcer and pregnancy.

Pharmacological treatment of pain is based on light or median analgesics but is always evaluated for expected pain based on the nature of the surgery, the expected pain and the current patient’s situation. As light analgesics, paracetamol, acetylsalicylic acid and NSAIDs are included. NSAIDs are considered unsuitable at risk of renal failure, increased bleeding tendency or expected bone formation as in reconstructive orthopedic surgery or ophthalmic surgery.

Paracetamol (Acetaminophen)

Paracetamol is a basic analgesic with relatively few side effects in therapeutic doses; regular treatment for adults is 1 g x 4 for a maximum of one week. Paracetamol may also be administered in elevated hepatic transaminases (<4 μkat/L) but not in elevated bilirubin, elevated PK or in acute liver failure. A combination of paracetamol and NSAIDs like ibuprofen may relieve mainly musculoskeletal pain from mild to moderate but also mild pain. In moderate to moderate pain, paracetamol in combination with NSAID or codeine may work well. An alternative to this combination is tramadol as monotherapy or in combination with paracetamol and possibly NSAIDs. The antiinflammatory effect of NSAID is best used in musculoskeletal pain where intravenous administration may also be appropriate postoperatively, eg with ketorolac or toradol. Patients at risk of gastrointestinal disorders should also be given a mucous membrane protection, eg in the form of omeprazole 20 mg x 1.

Paracetamol in Pain Therapy
 Loading Dose  Maintenance Therapy 
Weight(kg)Oral Solution 24 mg/mlTabletWeight(kg)Oral Solution 24 mg/mlTablet
20-2425mlT. 500 mg20-2417 ml x 4T. 500 mg x 3
25-3030 mlT. 750 mg25-3021 ml x 4T. 500 mg x 4
31-3440 mlT. 1000 mg31-3425 ml x 4T. 750 mg x 3
35-4240 mlT. 1000 mg35-4230 ml x 4T. 750 mg x 4
43-5050 mlT. 1250 mg43-5035 ml x 4T. 1000 mg x 3
50-7060 mlT. 1500 mg50-7040 ml x 4T. 1000 mg x 4
> 70 kg80 mlT. 2000 mg> 70 kg40 ml x 4T. 1000 mg x 4

Opiods

In moderate to severe pain, a morphine-based analgesia is often preferred in perioperative care. Per os, paracetamol plus, for example, oxycodone (OxyContin) may be given in the premedication and continued postoperatively. This regime can be supplemented with an adjuvant pharmacist if you expect neurogenic pain, for example in the form of gabapentin (300-1200 mg). Preparations used in the treatment of severe pain often consist of opioids such as morphine, ketobemidone, oxycodone, fentanyl or methadone. Additional opioids are available for those who are particularly interested.

The physiological effects of opioids are a multi-level pain inhibition, both in the brain, spinal cord and peripheral nerves. Opioids produce a strong analgesic effect primarily via opioid receptors in the CNS, via mu kappa or deltaopioid receptors. Endorphins and enkephalins have natural pain relieving effects in the CNS, as well as balancing of several different neurotransmitters, such as norepinephrine and GABA. Ultimately, dynorphins appear on my, and primarily receptors. Enkephalins act on delta receptors. Endorphins appear mainly on mu and kappa receptors, and beta-endorphins act on my and capillary receptors. Morphine provides good pain relief but can also cause anxiety, agitation, numbness, sedation, somnolence, dreams, coughing, nausea, itching, hallucinations, constipation and respiratory depression. Severe breathing depression is rarely seen without simultaneous sedation effect. Overdose is seen as an increasing somnolence and gradual development of motor inhibition, stupor and coma and respiratory depression. Opioids cause a decrease in heart rate and blood pressure, potent opioids often cause bradycardia. Breathing becomes slow and insufficient with mios, cyanosis, stupor and eventually cardiovascular collapse. Opioids are the most common cause of overdose deaths associated with addiction.

Long-term opioids also give a neuroendocrine effect in the form of inhibition of GnRH which may cause a decrease of FSH, LH and testosterone. Furthermore, CRF is inhibited, which causes a decrease of ACTH and cortisol. You also inhibit ADH via COPD. Opioids stimulate the release of prolactin. Among the physiological effects of opioids, a pupil-compulsive effect is observed with dose-dependent mios. You also get some histamine release and an inhibition of the immune system. Itching is common in overdose. There is a decrease in gastrointestinal motility and impaired secretion with a constipation effect. This is taken into account in the composition of the drug Targiniq, which in addition to an opioid also contains naloxone. Furthermore, the pressure increases in gall and urinary tracts, so morphine is less suitable for gallbladder or ureteral spasm.

Morphine

Morphine is a strong analgesic that shows affinity for cardiovascular, my- and deltaopioid receptors in the brain and spinal cord. It seems at these receptors as an opioid agonist without antagonistic effect. The therapeutic effect is predominantly analgesic and sedative. Morphine-based analgesics consist primarily of morphine hydrochloride but also occur as morphine sulfate or morphine sulfate pentahydrate. Partial agonists occur as buprenorphine or tapentadol. The medicaments are provided as capsules, tablets, solution for injection, infusion solution, gel, prolonged release tablets, transdermal patches or depot granules. Periods are also available for intranasal use and in lollipops for children! Common morphine preparations are Depolan, Dolcontin, Morfin, Morphine Scopolamine, Spasmofen and Oramorph.

The usual initial dose of Depolan is 10 mg x 2 peroral. This daily dose (20 mg) may be increased up to 50 mg/day if necessary. Parenterally, injection is usually given. Morphine 5 mg x 4-6.

Morphine Basic Therapy and Extra Doses in Pain Treatment

Long Acting AgentsPreparation FormNormal DosageAvailable preparations
Dolcontin® Slow-release Tablet5 mg x 2-3 up to 100 mg x 2-35 mg, 10 mg, 30 mg, 60 mg, 100 mg
Dolcontin® Slow-Release Granulate 20 mg x 2-320 mg
Depolan® Slow-release Tablet10 mg x 2-3 up to 100 mg x 2-310 mg, 30 mg, 60 mg, 100 mg, 200 mg
Short Acting AgentsAdditional Doses
Morphine Alternova Tablett 10-30 mg 4-6 times daily10 mg, 20 mg
Morphine Meda Tablett 10-30 mg 4-6 times daily10 mg, 20 mg
Morphine Meda Oral Solution10-30 mg 4-6 times daily2 mg/ml, 5 mg/ml
Morphine APL Suppository 5-30 mg 4-6 times daily5 mg, 10 mg APL
Morphine CapsuleOn special order*On special order* APL
Oramorph® Oral Solution2 mg/ml
Subcutaneous/Intravenous
Morphine Meda Injection 5-30 mg 3-6 times daily10 mg/ml
Morphine APL Injection 1-5-30 mg 3-6 times daily1 mg/ml, 20 mg/ml APL
Morphine Abcur Injection 5-30 mg 3-6 times daily10 mg/ml
Morphine AB Unimedic Injection 1-5 mg 3-6 times daily1 mg/ml
Long-term Targeted Drug DeliveryInfusion
Morphine Injection 1-5-30 mg 3-6 times daily1–20 mg/ml APL

The plasma half-life for morphine is 2-4 hours but varies in different formulations. The volume of distribution is approximately 3 liters / kg, plasma clearance is approximately 24 ml / min/kg. Morphine lacks dose-dependent kinetics. The estimated time for morphine is usually 10-30 minutes to full effect, which is often too slow. Morphine and its metabolites undergo enterohepatic circulation and metabolism in the liver. The most important metabolites are morphine-3-gluconuride lacking analgesic effect as well as morphine-6-gluconuride that have potent analgesic effects.

Elimination occurs primarily by glucuronidation and excretion of unreacted morphine in the urine (less than 0.1%). Toxic dose for adults without tolerance development is indicated at 40-60 mg for suppositories and 30 mg parenteral for injection. Letal dose for adults without tolerance development is indicated at 120-200 mg for suppositories and from 100 mg parenteral for injection. With increased tolerance development, you can tolerate doses of several hundred milligrams.

Hydromorphone

Hydromorphone (Palladon) occurs as an injection solution, capsules and depot capsules. 1.3 mg of hydromorphone hydrochloride has an analgesic effect corresponding to approximately 10 mg of morphine sulfate. The capsules can be swallowed whole or shared, the contents can be sprinkled over semi-solid foods.

Hydromorphone - Basic Therapy and Additional Doses

Long Acting AgentsPreparation formNormal DosageAvailable Preparations
Palladon® Slow Release Capsule1 capsule 2 times daily4 mg, 8 mg, 16 mg, 24 mg
Short Acting AgentsAdditional Doses
Palladon® Capsule1 capsule every 4:th hour1,3 mg, 2,6 mg
Subcutaneous/Intravenous
Palladon® Injection 1-2 mg s.c. every 3-4 hours inbetween 2 mg/ml, 10 mg/ml, 20 mg/ml, 50 mg/ml
Hydromorphone APL Injection 1-1.5 mg i.v. at 3-4 hour intervals. Shall be injected slowly for at least 2-3 minutes10 mg/ml, 20 mg/ml APL
Long-term Targeted Drug Delivery
Hydromorphone Injection 0.15-0.45 mg/hr
0.004 mg/kg body weight/hour
1 - 40 mg/ml APL

Methadone

Methadone is present as an oral solution, solution for injection and tablets. The usual initial dose is 10-30 mg. Initially, 5-10 mg 4-6 times daily are given for 1-2 days. For patients with high opioid tolerance, the usual initial dose is 25-40 mg. The dose is stepped up in increments of 10 mg per time over a period of three weeks, usually to 70 or 80 mg. The usual dose is 60-120 mg of methadone per day, but some may require a higher dose. Methadone solution for injection is given 0.5-1 ml intramuscularly or subcutaneously 1-3 times daily.

Methadone in Pain Treatment

Available preparations
Long Acting Agents
Preparation formNormal DoseAvailable Preparations
Metadon AbcurSlow-release Tablet5-20 mg x 2-35 mg, 10 mg, 20 mg, 40 mg
Metadon MedaSlow-release TabletThe usual initial dose is 10-30 mg. The usual daily dose is 60-120 mg.10 mg
Metadon DnEOral Solution1 mg/ml, 5 mg/ml
Methadone Martindale PharmaOral SolutionThe usual initial dose is 10-30 mg. The usual daily dose is 60-120 mg.2 mg/ml
Metadon PharmadoneOral Solution10 mg, 15 mg, 20 mg, 25 mg, 
30 mg, 35 mg, 40 mg, 45 mg, 
50 mg, 55 mg, 60 mg, 70 mg, 
80 mg, 90 mg, 100 mg, 110 mg, 
120 mg, 130 mg, 140 mg, 150 mg
Metadon Nordic DrugsOral Solution10 mg, 15 mg, 20 mg, 25 mg, 
30 mg, 35 mg, 40 mg, 45 mg, 
50 mg, 55 mg, 60 mg, 70 mg, 
80 mg, 90 mg, 100 mg, 110 mg, 
120 mg, 130 mg, 140 mg, 150 mg, 
160 mg, 170 mg, 180 mg, 190 mg 
och 200 mg
Subcutaneous/IntravenousInjection
Metadon RecipInjectable Solution5-10 mg 2-3 times/daily10 mg/ml

Codeine

Codeine is available in monotherapy tablets (25 mg) but is more common in various combination preparations like Citodon, Panocod, Spasmofen, Ardinex and Treo Comp. The codeine is an opiate that has much lower potency compared with morphine. The codeine exerts its analgesic effect by binding to my opioid receptors. The codeine itself also has a weak binding to kappa opioid receptors. A significant part of codein’s analgesic effect is likely to be explained by the codeine undergoing a biotransformation via the hepatic enzyme CYP-2D6 to morphine. Further more, the codeine via morphine can also be converted to morphine-6-glucuronide in the body. The analgesic effect of the codeine is therefore considered to be predominantly a morphine effect. Maximum codec concentration is usually reached within 1 hour. Plasma half-life is 3 – 4 hours. Codeine is metabolised primarily by glucuronidation but via a small metabolic pathway, O-demethylated codeine to morphine. This metabolism step is catalyzed by the enzyme CYP-2D6. Known slow metabolizers of the enzyme CYP-2D6 may have a lower effect due to lack of formation of morphine. Codeine is eliminated mainly via metabolism and excreted via the kidneys primarily as codeine, norcodeine and morphine conjugates as well as free codeine. Normally, about 5-15% of the code dose is converted by this enzyme via O-demethylation. The transformation of the codeine via this path is similar to the same polymorphic genetic regulation as 4-hydroxylation for debrisokin. This means that approximately 5-10% of a Scandinavian population exhibits slow codeine conversion, which also suggests that these individuals may have a worse analgesic effect of the preparation.

Petidin (Meperidine)

Petidin is only available normally as a solution for injections. Petidin was more common previously as peroperative analgesic. It was used inter alia during surgery on children where it worked particularly well in postoperative “shivering”. Petidin has an active metabolite in the form of norpetidine. Norpetidin is unsuitable for renal insufficiency. Petidin is a morphine-like analgesic which, in a dose of about 100 mg, has the same analgesic effect as 10 mg of morphine. At this dose, petidine develops the same type of side effects as morphine. The usual intravenous dose is repeated doses of 25-50 mg.

Fentanyl

Fentanyl is a potent analgesic used in continuous infusion for sedation and analgesia in intensive care. Fentanyl has a very small effect on the heart and circulation but has a strong respiratory depression effect. It is used as standard agent peroperatively under general anesthesia. Fentanyl is present as a solution for injection (Fentanyl, Leptanal), absorption tablets (Abstral), suction tablets (Actiq), nasal spray (Instanyl) and patches (Matrifen, Durogesic). Plaster for transdermal use is available in different strengths, usually 25, 50, 75 or 100 μg/h. These patches are usually changed after 3 days (72 hours). After use, the patches still have a significant residue of fentanyl left, so it has happened that they were sold and used for illegal abuse. Misuse of fentanyl patches occurs mainly by inhalation after evaporation. Medical use of fentanyl in patches has become a conventional way of treating chronic pain treatment. There is some risk of overdose associated with regional blockades that eliminate pain stimulation. Fentanyl patches are best suited for the treatment of pain in stable stages and not during titration.

Fentanyl in Advanced Pain Therapy

Available preparations
Long Acting Agents
Preparation formDosage: Transdermal dose/hour
Durogesic Transdermal Patch. Exchanged every 72 hours.12 μg/h, 25 μg/h, 50 μg/h, 75 μg/h, 100 μg/h
Matrifen Transdermal Patch. Exchanged every 72 hours.12 μg/h, 25 μg/h, 50 μg/h, 75 μg/h, 100 μg/h
Fentanyl Lavipharm Transdermal Patch. Exchanged every 72 hours.25 μg/h, 50 μg/h, 75 μg/h, 100 μg/h
Fentanyl Ratiopharm, Actavis, Mylan, OrionTransdermal Patch. Exchanged every 72 hours.
Fentanyl SandozTransdermal Patch. Exchanged every 72 hours.12 μg/h, 25 μg/h, 37,5 μg/h, 50 μg/h, 100 μg/h

Dosage: In the case of anesthesia, the usual initial dose of fentanyl to adults is 50-100-200 μg, 1-2 ml, which is slowly injected intravenously. The dose may be repeated 20-30-45 minutes after the initial dose. Secondary respiratory depression has been observed in cases where large doses were accumulated. Fentanyl should be used with caution in uncompensated hypothyroidism, lung disease, especially such as lowering lung capacity, alcohol abuse, liver or renal insufficiency. Tolerance and addiction can be induced. Fentanyl reduces the need for hypnosis necessary to maintain anesthesia, so the dose of hypnotic should be reduced.

Buprenorphine

Buprenorphine is an opioid agonist antagonist (partial opiate antagonist). Buprenorphine is available as travel tablets (Subutex, Suboxone, Temgesic, Buprenorphine) and as a depot patch (Norspan). Temgesic is also available as an injection of 0.3 mg/ml, the usual dose is 0.3-0.6 mg intravenously or intramuscularly. 0.3 mg buprenorphine given intramuscularly has an analgesic effect corresponding to approximately 10 mg of morphine with a duration of 6-8 hours. Buprenorphine is used for acute pain relief in the form of Temgesic, for the treatment of chronic pain as Norspan patch patch and for substitution treatment of opioid dependence in the form of Subutex, Suboxone and Buprenorphine. In substitution dependence, higher doses are compared to treatment of acute pain, 4-8-16-24 mg. It rarely pays to give more than 24 mg/day. Since buprenorphine is a partial antagonist, it is more difficult to overdose compared to normal morphine. The addictive effect is considered to be lower than for morphine. At high doses, a “ceiling effect” is achieved, where additional doses do not give more pain or anxiety. In case of overdose, the patient responds to naloxone but worse compared with the overdose of morphine. In breathing depression provide higher doses of naloxone and respiratory support.

Ketobemidone

Ketobemidone (Ketogan) occurs as tablets, suppositories and injections. Ketobemidone in its properties is very similar to morphine, both in dosage, effect and side effects. Some studies suggest somewhat less nausea with ketobemidone but this varies. Tolerance as well as physical and mental dependence can be developed. However, psychological dependence is rare, provided that ketobemidone is used for proper indication and in consultation between physician and patient. Ketogan (ketobemidone) is given in doses of 1-2.5-5 mg i v/i m if necessary, normaldos 4-6 times/day. Ketogan can also be administered orally 5 mg x 4 in chronic severe pain. Ketogan can be combined with Ketamin intravenously, 1.5 mg/ml 1-2 ml/t (“K + K”) in severe pain conditions.

Ketobemidone in Pain Therapy

Subcutaneous/IntravenousPreparation FormDosageAvailable Preparations
Ketogan Novum Injection Dosage individually, usual dose range is 5-7.5 mg intravenously / intramuscularly / subcutaneously every 3-5 hours5 mg/ml
Ketobemidon AB Unimedic**Injection Dosage individually, usual dose range is 5-7.5 mg intravenously / intramuscularly / subcutaneously every 3-5 hours1 mg/ml, 20 mg/ml
Short ActingAdditional Doses
Ketogan Novum Tablet1-3 tablets every 3-5 hours5 mg

Oxycodone

Oxycodone is available as prolonged-release tablets OxyContin (5/10/20/40/80 mg) as solution for injection, capsules, oral solution and tablets (OxyNorm, Oxicodon and Oxycodone). For injections, Oxycodone 10 mg/ml is usually used. Intravenously, 1-10 mg b.v. alternatively 2-5 mg/hr in continuous infusion. Oxycodone shows affinity to cardiovascular, my- and deltaopioid receptors in the brain and spinal cord. It seems at these receptors as an opioid agonist without antagonistic effect. The therapeutic effect is predominantly analgesic and sedative.

Oxycodone is also available in a preparation with naloxone to reduce the risk of constipation and severe overdosage in the form of prolonged-release tablets, Targiniq (naloxone/oxycodone). The usual dose of oxycodone release tablets is 10-20 mg x 2. Oxynorms that are not release tablets are given in doses of 5 mg if necessary, max x 4. Oxycodone has a good oral bioavailability of 60-87%. 10 mg oral oxycodone corresponds to approximately 20 mg morphine. The vast majority of patients do not need doses higher than 400 mg/day. Tapentadol is available as release tablets Palexia Depot (50, 100, 150, 200, 250 mg). Tapentadol is a strong analgesic with noradrenaline reuptake inhibitory effect and my opioid agonist effect. Tapentadol lacks active metabolites.

Oxicodone - Basic Therapy and Additional Dosage

Long Acting AgentsPreparation formDosageAvailable Preparations
OxyContin® Slow-release TabletUsually 5-10-20 mg every 12 hours.5 mg, 10 mg, 20 mg,
40 mg, 80 mg
Oxicodone Depot Acino Slow-release TabletUsually 10-20 mg every 12 hours10 mg, 20 mg,
40 mg, 80 mg
Oxicodone Depot ActavisSlow-release TabletUsually 5-10-20 mg every 12 hours5 mg, 10 mg, 20 mg,
40 mg, 80 mg
Oxicodone Depot EvolanSlow-release TabletUsually 10-20 mg every 12 hours10 mg, 20 mg, 40 mg
Oxycodone Depot Lannarcher, 1 A Farma, TevaSlow-release TabletUsually 5-10-20 mg every 12 hours5 mg, 10 mg, 20 mg,
40 mg, 80 mg
Short Acting AgentsAdditional Doses
Oxycodone Teva Capsule5-20 mg, max 6 times / day5 mg, 10 mg, 20 mg
OxyNorm® Capsule5-20 mg, max 6 times / day5 mg, 10 mg, 20 mg
OxyNorm® Oral Solution5 mg every 6 hours1 mg/ml, 10 mg/ml
Oxikodon Actavis CapsuleUsually 5 mg x 45 mg, 10 mg, 20 mg
Oxycodone G.L Film-coated TabletUsually 5 mg x 45 mg, 10 mg
Subcutaneous/IntravenousInjection
Oxynorm® Injection 1-10 mg times 4-6 per day10 mg/ml
Oxycodone Orion Injection 1-10 mg times 4-6 per day10 mg/ml
Long-term Targeted Drug DeliveryInfusion
Oxicodone Injection A starting dose of 2 mg / hour is recommended.1–40 mg/ml APL.
Dilute to 1 mg/ml in 9 mg/ml
(0.9%) sodium chloride, 50 ml/ml
(5%) glucose or water for injections

Tapentadol may be indicated in severe chronic pain when conventional treatment is insufficient. The substance is administered only peroral and is usually dosed twice a day at 12 hour intervals.

End of opioid treatment

All treatment with opioids should be limited in time to avoid adverse side effects, neuroendocrine effects and minimize the risk of addiction development. In the case of successful surgery, opioid therapy rarely needs to last for more than three weeks, often not more than one week. Already after a couple of weeks of opioid treatment, one can see a tolerance and withdrawal symptoms upon withdrawal. In order to avoid addiction development, treatment regimens can be changed and combinations of anesthesiological blockade techniques used and vary between medium and strong analgesics. In complicated pain management, the patient should always be referred to a reception with special skills in pain management. Successful treatment is often a cross-professional collaboration between several different specialties, with a good knowledge of underlying pathophysiology, and the patient’s personality and special needs are necessary. In the case of prolonged opioid therapy, the dose should be stepped down whenever possible. An appropriate dose reduction is approximately 20% per occasion at a few days intervals. In case of discontinuation of opioids, treatment with clonidine or ketamine may facilitate the release.


Conventional Treatment of Pain

Here are various treatments and doses for postoperative pain management. In general, pharmacological treatment is given in combination with different types of regional anesthesia. The following refers to postoperative standard treatment that is often combined with some regional blockade or infiltration anesthesia.

Here are some different suggestions on common pain management:

  • Paracetamol (Perfalgan, Alvedon, Panodil) 1 g x 4 to adults orally or intravenously (rectal administration is now unusual).
  • Ketobemidone (Ketogan) 1-2.5-5 mg per ml if necessary. Normaldos 4-6 times/day. Ketogan can also be given to us 5 mg x 4. (Ketogan can be combined with Ketamin intravenously, 1.5 mg/ml 1-2 ml/t (K + K)) in severe pain conditions.
  • Morphine (Morphine) 1-2-5 mg intravenously if necessary. Normal dose 4-6 times/day. Normal dose: 5 mg x 3.
  • Oxycodone (OxyContine) orally 10-20 mg x 2, 1-2-5 mg intravenously if necessary.
  • Oxycodone  (OxyNorm) orally 5 mg if required, max x 4.
  • Oxycodone + Naloxone (Targiniq) 20 mg/10 mg x 2.
  • Morphine in oral solution (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 x 1-3 orally .
  • Etoricoxib (Arcoxia) 60-120 mg x 1. Dose reduction in the elderly.
  • Parecoxib (Dynastat) 40 mg x 1.
  • Ketorolak (Toradol) 15-30 mg x 1.
  • Pregabalin (Lyrica) 150 mg x 2-3.

Analgesics for treatment of mild or moderate pain
Substance (generic)Label nameOral dosage for adults (mg)Parenteral dosage for adults (mg)
Mild analgesics
ParacetamolAlvedon, Panodil, Pamol, Paracetamol, Reliv

Perfalgan – i.v.
500 mg - 1000 mg x 3 - 41g x 3 - 4 (10 mg/ml)
Acetyl salicylic acid Bamyl, Magnecyl, Aspirin, Treo, Salicylic Acid, Trombyl500 mg x 3 - 4 
Acetyl salicylic acid + caffeineTreo, Bamyl koffein, Acetyl salicylic acid+ caffeine500 mg/50 mg x 3 - 4 
DiclofenacVoltaren, Diclofenac, Arthrotec, Eeze, Eezeneo, Ignorin, Solaraze, Dicuno50 - 100 mg x 2 
EtoricoxibArcoxia, Turox30-60-90 mg x 1 
ParecoxibDynastatN.A.40 mg x 1 - 2
KetorolakToradol 10-30 mg x 1 - 3
IbuprofenIbuprofen, Alindrin, Brufen, Burana, Ibumax, Ibumetin, Ifenin, Ipren, Nurofen, Pedea200 - 400 mg x 1 - 3 
KetoprofenOrudis, Siduro50 mg x 3 - 4 
NaproxenNaproxen, Alpoxen, Naprocur, Naprosyn, Pronaxen, Vimovo500 mg x 1 - 2 
CelecoxibCelebra100-200 mg x 1 
NabumetonRelifex1000 mg x 1 
IndometacinConfortid (supp)75-100 mg 1 - 2 ggr/daily 
TenoxicamAlganex20-40 mg x 1 
LornoxicamXefo8 mg x 1 - 2 
MeloxicamMeloxicam7,5 - 15 mg x 1 
Moderate analgesics
Codeine

 
Codein

 

 
25 - 50 mg x 2 - 3 
TramadolTramadol, Tiparol, Nobligan, Gemadol50 - 100 mg x 1 - 3 
Acetyl salicylic acid + caffeine + codeinTreo CompFizzies. 1 - 2 tabl. x 3 - 4 
Paracetamol + codeinCitodon, Panocod, Codalvonil500 mg/30 mg 1 - 2 tabl. x 1- 3 
Paracetamol + orfenadrinNorgesic450 mg/35 mg 1-2 tabl. x 1 - 4 
Ibuprofen + codeinArdinex200 mg/30 mg: 1-2 tabl. x 1 - 4 
Strong analgesics
Morphine

 
Depolan, Morfin, Morfin-Skopolamin, Dolcontin, Oramorph, Spasmofen

 

 
Tablet or oral solution

10 mg x 2

10-30 mg x 4 - 6
2-5-10 mg i v/i m as needed
Ketobemidon

 
Ketogan

 
5 mg x 45 - 10 mg i m as needed

1-2,5–5 mg i.v. as needed. Normal dose 4–6 times/day.

1,5 mg/ml 1 - 2 ml/h
Meperidine

 
Petidin

 
-50 - 100 mg i.m.
Oxycodone

 
OxyContin, OxyNorm, Oxikodon, Oxycodone

 
10 - 20 mg x 2

5 mg vid behov, max x 4
2-5-10 mg i.v.

1-2-5 mg intravenöst vid behov.
Fentanyl

 
Fentanyl, Leptanal, Durogesic, Matrifen25/50/75/100 μg/hour transdermally0,1 - 0,2 mg i.v.
Diamorphine

 
Heroin

 
605-10-20 mg
Methadone

 
Metadon, Methadone

 
5 - 20 mg x 2-310 mg
Hydromorphone

 
Palladon (Dilaudidatropin, Opidol)

 

 
4 - 24 mg x 21 - 2 mg x 6 s.c.

1 - 1,5 mg i.v. x 3 - 4
Buprenorphine

 
Temgesic, Subutex, Suboxone4 - 8 mg (max 24 mg/d)

 
0,3 - 0,4 mg
TapentadolPalexia Depot50 mg x 2 (max 500 mg/day) 
Oxycodone + NaloxonTarginiq20 mg/10 mg x 2
40 mg/20 mg x 2
80 mg/40 mg x 2
 
Metylscopolamine + codein + morphine + papaverinumSpasmofen 1 - 2 ml 1 - 2 ggr/day

Supp: 1 supp x 1 - 4/day

Treatment of mild to moderate pain
Substance (generic)Label nameOral dosageAnesthesiological comment
ParacetamolAlvedon, Panodil500-1000 mg x 2-3Paracetamol may also be given in patients with lightly elevated liver transaminases (<4 μkat/L), but not in acute liver failure. Upper limit 4 g/day, max for one week.
Salicylic acidMagnecyl, Aspirin,500 mg x 3-4Caution to young children or in dehydration. Avoid gastritis or ulcer. No contraindication for spinal or epidural anesthesia.
Paracetamol + IbuprofenPanodil + Brufen1000 mg x 2 + 400 mg x 2Look at paracetamol comment.

 
NaproxenNaprosyn500 mg x 2NSAID:s should not be given in orthopedic surgery or ENT surgery.

Treatment of moderate pain
Generic substanceLabel nameOral dosageAnesthesiological comment
Paracetamol + IbuprofenPanodil + Brufen1000 mg x 2 + 400 mg x 2Paracetamol may also be given to patients with lightly elevated liver transaminases (<4 μkat/L), but not in acute liver failure. Upper limit 4 g/day, max for one week.
Paracetamol + EtoricoxibPanodil + Arcoxia1000 mg x 2 + 60 mg x 1Look at paracetamol comment.
Salicylic acid + caffeine + codeinTreo CompFizzies. 1-2 tabl. x 3-4Risk of addiction development.
Paracetamol + codeinCitodon, Panocod, Codalvonil500 mg/30 mg 1-2 tabl. x 1-3Some risk for a sedative effect.
DiclofenacVoltaren, Diclofenac, Arthrotec, Eeze, Eezeneo, Ignorin, Solaraze, Dicuno50-100 mg x 2High risk of gastrointestinal discomfort during prolonged treatment (> 5 days). NSAIDs should not be given in orthopedic surgery or ENT surgery.

Treatment of moderate to severe pain
Generic substanceLabel nameOral dosageAnesthesiological comment
Salicylic acid + caffeine + codeinTreo CompFizzies. 1-2 tabl. x 3-4Risk of addiction development.
Paracetamol + codeinCitodon, Panocod, Codalvonil500 mg/30 mg 1-2 tabl. x 1-3Some risk for sedation
TramadolTramadol, Tiparol, Nobligan, Gemadol50-100 mg x 1-3Some risk of respiratory depression. Risk of addiction development.
Paracetamol + Ibuprofen (alt. other NSAID)Panodil + Brufen1000 mg x 2 + 400 mg x 2Look under paracetamol.

 
DiclofenacVoltaren, Diclofenac, Arthrotec, Eeze, Eezeneo, Ignorin, Solaraze, Dicuno50-100 mg x 2High risk of gastrointestinal discomfort during prolonged treatment (> 5 days). NSAIDs should not be given in orthopedic surgery or ENT surgery.

Treatment of severe pain
Generic substanceLabel nameOral dosageAnesthesiological comment
Paracetamol + codeinCitodon, Panocod, Codalvonil500 mg/30 mg 1-2 tabl. x 1-3Some risk for somnolence.
TramadolTramadol, Tiparol, Nobligan, Gemadol50-100 mg x 1-3Some risk of respiratory depression. Risk of addiction development.
Ketobemidon

 
Ketogan

 
5 mg x 4.Some risk of respiratory depression. Risk of addiction development.
Oxycodone

 
OxyContin, OxyNorm, Oxikodon, Oxycodone

 
10-20 mg x 2.

5 mg vid behov, max x 4.
Some risk of respiratory depression. Risk of addiction development.
Fentanyl

 
Transdermal patch: Durogesic, Matrifen25/50/75/100 µg/tim transdermallyRisk of overdose in combination with other opioids or regional blockades.
Oxycodone + NaloxonTarginiq20 mg/10 mg x 2
40 mg/20 mg x 2
80 mg/40 mg x 2
Risk of addiction development.

Treatment of very severe pain
Generic substanceLabel nameOral dosageParenteral dosageAnesthesiological comment
Ketobemidon

 
Ketogan

 
5 mg x 45-10 mg i m as needed.

1-2,5–5 mg i.v. as needed. Normal dose 4–6 times/day.

1,5 mg/ml 1-2 ml/h
Risk of overdose in combination with other opioids or regional blocks.
Oxycodone

 
OxyContin, OxyNorm, Oxikodon, Oxycodone

 
10-20 mg x 2

5 mg as needed, max x 4
2-5-10 mg i.v.

1-2-5 mg intravenously as needed
Risk of overdose in combination with other opioids or regional blocks.
Morphine

 
Depolan, Morphine, Morphine-Scopolamin, Dolcontin, Oramorph, Spasmofen

 

 
Tablet or oral solution

10 mg x 2

10-30 mg x 4-6
2-5-10 mg i v/i m as neededRisk of overdose in combination with other opioids or regional blocks.
TapentadolPalexia Depot50 mg x 2
Fentanyl

 
Transdermal patch: Durogesic, Matrifen25/50/75/100 µg/tim transdermallyRisk of overdose in combination with other opioids or regional blocks.

Adjuvant Pharmacology in the Treatment of Severe Pain
Generic substanceLabel nameOral dosageParenteral dosageAnesthesiological comment>
PregabalinLyrica150 mg x 2-3 Risk for development of addiction
GabapentinNeurontin300 mg x 3 May provoke somnolence in high doses.
ClonidineCatapresan75 µg x 3-6 (Unregistered, licensing is available)1 µg/kg perop i.v.Some risk for bradycardia and hypotension.
BaclofenLioresal5 mg x 3300-800 µg/day in a continous intrathecal infusion

 
Note that it may cause respiratory depression during intrathecal administration.

Kan användas för GHB associerad abstinens.
KetaminKetalar Ketamin intravenously, 1,5 mg/ml 1-2 ml/h (K + K).

 
Low dose ketamine in infusion adds additive pain relief to opioids without the risk of confusion or hallucinations.
AmitriptylineSaroten, Tryptizol25 mg x 1-3 Anticholinergic side effects are common as well as orthostatism.
Duloxetin Cymbalta60 mg x 1 May cause blood pressure increase.
BetametasonBetapred8 mg x 2 Adrenal insufficiency during long term treatment. Blood sugar elevations.

Proposed extra doses of opioids for treatment of breakthrough pain. The doses refer to simple additional doses.
Fentanyl transdermal µg/timMorphine mg orallyOxycodone mg orallyHydromorphone mg orallyMorphine sc/ivOxycodone sc/ivHydromorphone mg sc/iv
125-105 55 
2510101,35-105-10 
5025-30202,610-1510-152-3
7540303,915153
10050405,220204-5
125-15070507,8–10,425255-6
175-20010070 30306-8
250-300150100 505010-12
350-400200150 60-7060-7014-16


Equipotencies of Opioids

Conversion Table for Opioids
Conversion GuideExtradose constitutes approximately 1/6 of the daily dose:        
TramadolBuprenorphineTapentadolMorphine/KetobemidonMorphine/KetobemidonOxicodoneOxicodoneHydromorphoneHydromorphoneFentanyl
OralTransdermallyOralOralsc/ivOralOralsc/ivsc/ivOralOralsc/ivsc/ivTransdermally
Daily Dose mgμg/hDaily Dose mgDaily Dose mgExtra dose mgDaily Dose mgExtra dosemgDaily DosemgExtra dose mgDaily Dose mgExtra dose mgDaily Dose mgExtra dose mgDaily Dose mgExtra dose mgμg/h
1001050202,5 - 5 7 - 10 1 - 2 101 - 2 7112
2002050405 - 10 15 - 20 2 - 5 202 - 5 1524 - 8 1.32 - 4 ≤1 12
30030100601020 - 30 3 - 5 3052038 - 12 2.64 - 6 ≤1 25
400402008010 - 15 30 - 40 5 - 7 405 - 10 30512 - 16 2.66 - 8 125
2001001535 - 50 6 - 8 505 - 10 35614 - 20 2,6 - 3,9 7 - 10 1 - 2 37
3001202045 - 60 7 - 10 601045718 - 24 2,6 - 3,9 9 – 12 250
4001602560 - 80 10 - 15 8010 - 15 601024 - 32 3,9 - 5,2 12 - 16 2 - 3 50
5002204080 - 110 15 - 20 110208010 - 15 32 - 44 5,2 - 7,8 16 - 22 3 - 4 75
32055120 - 16020 - 25160251202048 - 647,8 - 10,424 - 324 - 6100
40070150 - 200 25 - 35 200351502560 - 80 10,4 - 13 30 - 40 5 - 7 125
50085185 - 250 30 - 40 250401853074 - 100 12 - 17** 37 - 50 6 - 9 150
580100* 215 - 290 35 - 50 290502153586 - 116 14 - 19** 43 - 58 7 - 10 175
680115** 255 - 340 45 - 55 3405525545102 - 136 17 - 23** 51 - 68 9 - 12 200
760125** 285 - 380 50 - 65 3806528550114 - 152 19 - 25** 57 - 76 10 - 13 225
860145** 320 - 430 55 - 70 4307032055128 - 172 21 - 29** 64 - 86 11 - 15 250
940155** 350 - 470 60 - 80 4708035060140 - 188 23 - 31** 70 - 94 12 - 16 275
1040175** 390 - 520 65 - 85 5208539065156 - 208 26 - 35** 78 - 104 13 - 18 300
*) APL Order in capsule form**) APL can investigate the possibility of producing other strengths and preparations.
Think of:Each patient should be dosed individually.Careful conversion at higher doses.
Replacement of opioid in a well-pain-relieved patient with troublesome side effects:Calculate the equivalency dose according to the conversion guide. Reduce the dose of the new opioid to 50-75% of the equivalency dose. Replace the swab without escalating the previous opioid. (Pharmaceutical Agency's guidelines for pain in end of life, year 21, No. 6, Dec 2010).
Equipotencies of Opioids in Parenteral or Oral Preparations
Generic substanceOral dose (mg)Parenteral dose (mg)Oral Bioavailability (%)
Morphine301035 (15-55)
Ketobemidon301035 (20-60)
Meperidine40010030-60
Oxycodone151060-87
Codein20013060-90
Fentanyl 0,100< 2
Heroin605< 10
Methadone101060-90
Hydromorphone4,51,535-80
Buprenorphine0,4-0,80,3-0,4low
Alfentanil 0.5-0,75 
Equipotencies of Different Opioids
Morphine
mg orally
Oxycodone
mg orally
Hydromorphone
mg orally
Morphine
sc/iv
Oxycodone
sc/iv
Hydromorphone
sc/iv
Fentanyl
patch μg/h
6040820-3020425
120801640-6040850
2401603280-120801675-100
32020040100-16010024100-125
40024054130-20012026150
60040080200-30020040200
800480 260-40024050250-300

Pharmacokinetics of Opioids

Terminal half lifes and metabolites
Generic substanceLabel nameT ½ (h)Metabolites
MorphineMorphine2-4 hM6G, M3G
KetobemidonKetogan2-4 hNej
MeperidinePetidin3-4 hNorpetidin
OxycodoneOxycontin, Oxynorm2-6 h
CodeineCodeine and others3-4 hMorphine
FentanylFentanyl, Leptanal, Durogesic, Matrifen3-4 hNej
DiamorphineHeroin0,5 hMorphine
MethadoneMethadone6-150 hMorphine
HydromorphoneDilaudidatropin, Opidol2-4 h
BuprenorphineTemgesic, Subutex, Suboxone3-5 h 

Fentanyl (Fentanyl®)

Solution 50 μg/ml – about 100 times the potency of morphine. Intubation dose for general anesthesia: 1 – 8 μg/kg i.v. (70 kg = 70-600 μg = 2 – 12 ml). For children 2 – 12 years, 1 – 3 μg/kg are given in combination with inhalation anesthesia.

Alfentanil (Rapifen®)

Solution 0.5 mg/ml, approximately 25 times the potency of morphine (1 ml Rapifen ≈ 12.5 mg morphine). Max effect within 90 sec – duration 5 – 10 min. May give muscle rigidity especially at high doses. Dose in short painful intervention: 0.25 – 0.5 mg in v – repeat v b. Optimal intubation dose: 20 – 40 μg / kg i.v. (70 kg = 1.5 – 3 mg = 3 – 6 ml)

Remifentanil (Ultiva®)

Intubation dose: 0.25 – 0.5 μg/kg/min (TCI 4 – 8 ng/ml) + Propofol 1 – 3 mg/kg. Maintenance light surgery: Remifentanil (Ultiva)  0.15 – 0.25 μg/kg/min (TCI 4 – 6 ng/ml) + Propofol 4-6 mg/kg/h (TCI 2 – 3 μg/ml). Maintenance deep surgery: Remifentanil (Ultiva)  0.2 – 0.5 μg /kg/min (TCI 5 – 10 ng/ml) + Propofol 6-8 mg/kg/h (TCI 3 – 4 μg/ml). Titrate down/close propofol when the skin is sewn; turn off Remifentanil (Ultiva) earliest at the last stitch.


Ketamin for pain modulation

Ketamine/Ketanest (Esketamine) in low dose for pain treatment

Ketamine (S and R, see below), which is an NMDA receptor blocker, modulates both surgically induced and drug-induced hyperalgesia at doses much lower than the doses required for general anesthesia. (Hyperalgesia = increased response in a painful direction.) Ketamine has an opioid-saving effect.

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

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

Indications

  • Expected postoperative pain problem
  • Amputation (upper, lower extremity)
  • Acute phantom pain
  • Patients with long-term pain + acute pain
  • Ongoing high opioid medication (opioid tolerant patient) + acute pain
  • Abuse in the history (when avoiding opioids) + acute pain

Dosage Perioperative

Ketanest Infusion; low-dose infusion (in addition to local, regional or general anesthesia)

  • Start of operation: 0.1 – 0.3 mg/kg bolus iv
  • Maintenance dose: 0.1 – 0.3 mg/kg/h iv
  • After the last suture is set: 0.03 mg/kg/h iv
  • Postoperatively for 12 – 72 hours: 0.03 – 0.06 mg/kg/h intravenously. 

Postoperatively inserted Ketanest or Ketanest for unoperated 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, given over 12 – 72 hours.

Ketamin infusion dosing schedule

Infusion rate in ml/h at different body weights
 
Patient's Weight (kg):40 kg 50 kg 60 kg 70 kg 80 kg 90 kg 100 kg 110 kg
Ketanest dosage (mg/kg/h)
0,03 mg/kg/h: 1.21.51.82.12.42.733.3
0,04 mg/kg/h 1.622.42.83.23.644.4
0,05 mg/kg/h 22.533.544.555.5
0,06 mg/kg/h 2.433.64.24.85.466.6
0,1 mg/kg/h 4567891011
0,2 mg/kg/h 810121416182022
0,3 mg/kg/h 1215182124273033
NOTE! Ketanest and barbiturates (eg Tiopental) should not be administered in the same entry (chemically incompatible).
Dilution: 2 ml Ketanest 25 mg/ml + 48 ml NaCl 9 mg/ml = giving 50 ml Ketanest 1 mg/ml. [Infusion is given iv with pump (50 ml syringe). Shelf life after mixing: not more than 12 hours.]

Drug combinations and recommendations

  • Ketanest is preferably combined with low dose midazolam, or other benzodiazepine.
  • Increased salivation is common during treatment with Ketanest; – give Glycopyrronium (Robinul) or Atropin iv.
  • There are no significant interactions when Ketanest is given in low dose, which means that other prescribed analgesics (paracetamol, NSAIDs, Cox-2 inhibitors, opioids, clonidine, gabapentin, pregabalin, local anesthetics) should be given.
  • Ketanest should not be mixed with morphine in the same iv-PCA pump.
  • Ketanest is not recommended as iv-PCA.
  • The seizure threshold may be reduced in combination with xanthine derivatives (for example, aminophylline and theophylline) and therefore these combinations should be avoided.
  • The medicine should not be used with Ergometrine (Ergotamine).

Monitoring and documentation

  • Patients with IV low dose infusion Ketanest are usually monitored at the department of postop/ICU.
  • Document sedation rate, RASS/VAS, respiratory rate, SaO2, heart rate and blood pressure.
  • Ask for nightmares, hallucinations and vision disorders in connection with monitoring.

Side effects

  • Nightmares, hallucinations or visual disturbances appear to be insignificant in low dose infusion and/or in single bolus. Give 1 – 3 mg midazolam iv (or other benzodiazepine) as needed.
  • Increased salivation. Give glycopyrronium (Robinul) or atropine iv.

Contraindications

  • Hypersensitivity to the active substance or to any of the excipients.
  • Eclampsia and pre-eclampsia.
  • Patients in whom an increase in intracranial pressure is a serious risk.
  • Patients in whom an increase in blood pressure is a serious risk.

Warnings and Caution

  • Tachyarrhythmias
  • Untreated hypertension
  • Increased intracranial pressure, head injury or hydrocephalus
  • Increased intraocular pressure (eg, glaucoma) or eyeball damage
  • Alcohol intoxication
  • Psychiatric history (eg 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. The Chef 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 or N-methyl-d-aspartate receptor antagonists in postoperative pain management. Current Opinion in Anaesthesiology, 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, Zelko 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 or ketamine for prevention of postoperative hyperalgesia after remifentanil-based anesthesia 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

Epiduralanestesi för postoperativ smärtlindring

Continuous Epidural Analgesia for Postoperative Pain Relief

Continuous epidural anesthesia for postoperative pain reliefStandard mixture of local anesthetics plus opioid is usually given at a dose of 4-16 ml /hour
Local anestheticOpioidAdrenaline additionDosage
Bupivacaine 1,0 mg/mlFentanyl 2 μg/ml +Adrenaline 2 μg/ml8-14 ml/hour (Breivik's blend/BFA)
Bupivacaine 2,5 mg/mlSufentanil 0,5 μg/ml8-12 ml/hour
Bupivacaine 2,5 mg/mlMorphine Special 0,4 mg/ml5-10 ml/hour
Bupivacaine 1,0 mg/mlSufentanil 1 μg/ml8-16 ml/hour
Ropivacaine 2 mg/mlSufentanil 1 μg/ml8-16 ml/hour
Ropivacaine 2 mg/mlMorphine Special 0,4 mg/ml5-10 ml/hour
Levobupivacaine 1,25 mg/mlSufentanil 1 μg/ml8-16 ml/hour
Levobupivacaine 1,25 mg/mlMorphine Special 0,4 mg/ml 5-10 ml/hour
Continuous epidural anesthesia without opioids:
Bupivacaine 2,5 mg/ml5-7,5 ml/hour
Ropivacaine 2 mg/ml6-14 ml/hour
Levobupivacaine 1,25 mg/ml10-15 ml/hour
Levobupivacaine 2.5 mg/ml5-7,5 ml/hour

Epidural opioids

Registered drugs for epidural use in Sweden are Morphine Special (morphine) and Sufentanil (Sufenta). Even fentanyl (Fentanyl) is used epidurally. The drugs are given continuously in infusion or intermittent in bolus, 3-4 times/day. Morphine can be given three times a day or in continuous infusion.

  • Morphine 3-4 mg x 3 in EDA. Initially, up to 5 mg of morphine hydrochloride may be given if necessary. If necessary, a dose of 2-4 mg of morphine hydrochloride may be given when the effect of the first dose declined, usually after 6-24 hours.
  • Fentanyl 2 μg/ml, 4-12 ml/h should be given in continuous infusion with or without local anesthetic agents.
  • Sufentanil 1 μg/ml, 8-16 ml/h should be given in continuous infusion with or without local anesthetic agents. Sufentanil can also be given in bolus without local anesthetic 25 μg epidurally x 3-4.

EDA controls

  • Heart rate and blood pressure every 4 hours
  • Pain intensity (VAS) every 4 hours
  • Motor control of the arms and legs (en. Bromage) every 4 hours
  • Injection site 3 times/day
  • Respiratory rate every 4 hours at opioid supplement
  • Sedation rate was 4 hours at opioid supplement.

The above controls can be performed every 6 hours after a day without dose increase. Extra check 10 min and 30 min after increased infusion rate or epidural bolus dose. Extra controls 30 min and 60 min after reactivation of EDA. Extra controls 2 times/hour for 2 hours when sedative or respiratory depression medication. Dosage and bolus doses are given only after contact with a pain nurse or anesthetist. Aggregate should be changed after 3 days.

EDA och anticoagulants

At least 10 hours between given LMWH (Klexane® or Fragmin®) and EDA insertion or catheter adjustment. EDA is withdrawn > 2 hours before or > 10 hours after given LMWH. Control of motoring (Bromage) after 6, 8 and 12 hours after the extracted epidural catheter. Documented! CAD should remain 6 hours after withdrawal of epidural catheter.

EDA complications

Epidural hematoma is a rare but serious complication that requires immediate treatment. Symptoms: Pain in the back and sometimes in the legs as well as increasing paralysis in the legs. Epidural abscess is another serious complication that requires immediate treatment. Symptoms: Fever, general discomfort, back pain and increasing paralysis of the legs. In case of suspicion of the above complications, the infusion in the EDA should be discontinued and anesthetist will be contacted immediately!

Controls of patients with EDA

Controls of motor skills, sedation,
nausea and itching
Score0 p1 p2 p3 p
Motor skills according to BromageFull mobility in hip, knee and footCan touch the knee and hip joint, but do not raise the legCan touch the ankleCannot touch the knee or ankle
Motor skills in the armsNormal motor skills in armsWeakness in arms
Sedation DegreeAbsolutely awakeDrowsy, light sedationSedated but possible to awakeDeep sedation, not possible to awakeS: Sleeping a natural sleep
NauseaNot nauseousNon treated nauseaTreating nauseaVomiting
ItchingNo itchingUntreated itchingTreated itching

 


Patient Controlled Analgesia (PCA)

Patient controlled analgesia (PCA) constitutes of a continuous or intermittent infusion of pain relief (normally Morphine), with the ability for the patient to self-administer extra doses at their own request, bolus doses. PCA can be administered intravenously, subcutaneously or epidurally. Common pumps used are GEM-star, CAD or Deltec. The method allows for a fairly even plasma concentration of added drugs with the ability to control the treatment following the patient’s activities and the need for pain relief. The method smooths out the large inter-individual differences between patients in the need for postoperative pain relief. Usually, PCA is used for 2-4 days after medium and large surgical procedures. Risk groups are elderly patients, heavily overweight, patients with respiratory insufficiency, drowsiness or unhealthy patients, patients with addiction problems.

Standardinfusion PCA

Morphine 1 mg/ml, 1-2 ml, 1-2 mg in bolus with a lock time of 6-10 minutes. A common setting is 1 ml (1 mg) per bolus with a lock time of 6 minutes, giving a maximum supply of 10 mg / h and 10 ml. A barrier volume after 4 hours is 40 ml if requested by the pump. Ketobemidon (Ketogan®) 1 mg/ml and Ketamine can also be used. The goal of PCA is VAS <4 and 1-2 bolus doses per hour. In the care department, it is important to supervise and check every four hours of VAS, respiratory rate, sedation rate, nausea, itching, bladder function. Additional controls must be made if the doses are increased with controls every 30 minutes for two hours. In case of insufficient pain relief, dosage doses can be given every 10 minutes until good pain relief is achieved. Consider dose increase of bolus doses by 25-50 percent. If the number of PCA doses exceeds 3 per hour, the bolus dose is increased. If the number of bolus doses required exceeds the dose given, the bolus dose is increased. Consider adjuvant pain management.

Safety checks in the case of PCA and intravenous opiod treatments

Every fourth hour the following should be checked:

  • VAS
  • Sedation Degree
  • Respiratory rate
  • Nausea
  • Itching

Bladder ability is checked every 8 hours. If the patient does not have KAD, residual urine is checked once a day. Extra controls 30 min after increased dose or addition of sedative or respiratory depression medication. Aggregate changed after 3 days


Patient Controlled Epidural Anesthesia (PCEA)

Patient controlled epidural anesthesia (PCEA) contains epidural continuous infusion plus patient controlled bolus doses or intermittent infusion with bolus doses only, with the ability for the patient to self-control the treatment at his own request in the form of small bolus doses. PCEA is given epidural and the aim is to provide better pain relief with smaller doses in total compared with continuous continuous infusion. The method allows the patient to control the treatment for own activities with mobilization and the need for pain relief. The method smooths out the large inter-individual differences between patients in the need for postoperative pain relief. Typically, PCEA is used for 2-4 days after medium and large surgical procedures and in childbirth analgesia. PCEA is well suited for childbirth analgesia and has been shown to provide better pain relief compared with conventional EDA. In childbirth analgesia, PCEA can be given either as self-administered bolus doses or as continuous infusion plus PCEA. When setting bolus doses only, these are given in larger doses than in combination with continuous continuous infusion with PCEA, for example 5 ml instead of 2 ml per dose.

Risk groups are elderly patients, heavily overweight, patients with respiratory insufficiency, severely injured or unhealthy patients. In childbirth EDA, risk groups are predominantly overweight and patients with preeclampsia.

Common pumps used are GEM star, CADD or Deltec.

Standardinfusion PCEA

Continuous infusion of 4-10 ml/h. Bolusdos 2 ml, shutter time 10 minutes and maximum dose of bolus doses per hour adjusted to 4. At max 10 ml / t infusion with max. Pressure 4, a total dose of 18 ml/h is given, which is calculated as the maximum dose.

Some suggestions for combination therapy with PCEA

  • Bupivacaine (Marcain®) 1.0 mg/ml + Fentanyl 2 μg/ml + Adrenaline 2 μg/ml. Dosage: 4-10 ml/h, bolus dose 2 ml.
  • Ropivacaine (Narop®) 2 mg/ml, + Sufentanil 1 μg/ml, 3-10 ml/h, bolus 2 ml during surgery. The next morning you can switch to Ropivacaine (Narop) 1 mg/ml + Sufenta 0.5 μg/ml to allow patient patient mobilization according to the operator’s instructions. This infusion may continue for a further few days.
  • Ropivacaine (Narop®) 2 mg/ml + Sufentanil 1 μg/ml + Clonidine 3 μg/ml. 3-10 ml/h, bolus 2 ml.

In postoperative/ICU obstetrics treatment, the number of doses requested, the number of doses delivered and the total dose given are recorded and documented. The goal of PCEA is VAS <4 and 1-2 bolus doses per hour. In the care department, it is important to supervise and check every four hours of VAS, respiratory rate, sedation rate, nausea, itching, blister function. Additional controls must be made if the doses are increased with controls every 30 minutes for two hours. In case of insufficient pain relief, dosage doses can be given every 10 minutes until good pain relief is achieved. If the number of PCEA doses exceeds 3 per hour, the continuous infusion is increased. In case of insufficient pain relief at the maximum dose, consider adjuvant pain treatment or to change the epidural. In the treatment of patients with mild preeklampsi, coagulation tests should be checked no later than 6 hours prior to the establishment of an EDA. In case of severe eclampsia, these samples (PK/INR/APT(T)/TPC) should not be older than 2 hours.


Opioids in chronic non-cancer related pain

Written by Christian Simonsberg, Pain physician, Psychiatrist, SU/East, Anders Mellén, Chairman of the Therapy Group.

Background

Prolonged pain generally refers to pain with a duration of more than 3-6 months. This pain is often multifactorial. For advice on non-pharmacological treatment, see the therapy group’s website: www.vgregion.se/lakemedel/smarta. Treatment with opioids of long-term non-cancer related pain should always be regarded as a time-limited therapy. When the acute nociceptive pain transitions into a chronic condition, this is a new condition with changes in the central nervous system as a consequence. This means that you need to decide on how continued treatment will look. Treatment with opioids, regardless of substance, may be considered for selected cases where reasonable attempts to etiological and other symptomatic treatment have been made. The support for continuous pain relief in prolonged opioid treatment is evidently weak. Liberal prescription of opioids to many patients poses a risk of increasing the number of cases with serious adverse events including development of addiction.

Before prescription

Before opioid administration, risk factors for abuse and future addiction development should be considered, such as low age, psychological ill health, dependency issues in history, high dosage, multiple prescribers and/or low compliance to the ordinance. Before prescribing should also be judged if the patient has mental and/or somatic diseases where opioids can present health risks. Consultation or referral to a pain specialist is recommended in these cases.

Drug treatment

Decisions on treatment should relate to a pain analysis, assessing what causes the pain and whether it is reasonably suitable for opioid therapy. Evaluate with the patient what functional and quality of life parameters, in addition to pain relief, the treatment intends to improve and what should be the goal of the treatment. Evaluate whether there may be elements of neuropathic and/or inflammatory pain that may be treated separately and if there is adjuvant treatment that should be initiated, e.g. tricyclic antidepressants. Also, evaluate whether different forms of non-pharmacological treatment can be a complement, or be a more appropriate alternative, to the pharmacological treatment. Please allow the patient to test physical activity/exercise, acupuncture, TENS and/or heat. Patients often also need support and knowledge to handle their lives with pain present. For more information, see extended therapy advice on non-pharmacological treatment on the therapy group’s website (see column 1).

Treatment responsibility

When you start treatment with opioids you have treatment responsibility. Recipes for opioids should be written from one and only unit of named physicians to be informed by the patient. In addition, the patient should be informed that prescriptions will not be written from other entities without agreement and that the prescription will be followed. Prescription physician has responsibility for treatment until an accepting and informed colleague takes over the prescription. It is important that there is a plan for how the treatment will look and when follow-up occurs. The patient should have access to any informed doctor who may prescribe to such an extent that the patient does not end up in withdrawal, or have pain breakthrough, pending contact with the treatment manager. Written contracts can be used for additional clarity regarding what applies to the prescription.

Prescription

In all prescriptions of opioids, the patient’s consent to the prescriber’s access to the pharmaceutical list should be regarded as a requirement. Strive for long-term preparation and if short-term planning is planned, you will need to make clear how much can be used. Some preparations have a maximum dose, but most “strong” opioids have no given maximum dose. Therefore, before the start of treatment, you must have a plan for how high doses are reasonable. Determine the lowest possible dose and avoid prescribing large packages. The amount of prescription should match the follow-up time, i.e. prescribe only the amount included for scheduled follow-up to reduce the risk of overdose. Take into account the possibility of expedition intervals. Avoid concurrent treatment with benzodiazepines and opioids, as shown in association with increased risk of death due to toxicity in combination of these preparations.

Dosage

Begin with a low dose and evaluate each increase step by step. Note that the maximum dose of codeine 240 mg/day (= T. Citodon 2 × 4) is converted to approximately 24-36 mg morphine/day, but due to genetic variations and/or drug interactions, the amount of morphine obtained may vary considerably between different individuals. Codeine is therefore not recommended. Also note that oxycodone in oral treatment is 1.5-2 times as potent as morphine. If the patient has tested an opioid in the daily dose corresponding to 60 mg morphine/40 mg oxycodone orally without effect, there is little chance of success with pain relief, even if you continue to increase the dose. If you have not had effect after one month’s treatment, it is also unlikely to be effective by prolonging the treatment. In case of chronic non-cancer-related pain, the daily dose should rarely exceed 90 mg morphine/60 mg oxycodone per day. The potential painful gain of escalation over these doses is small in relation to the risk of tolerance development and addiction. If the patient is judged to benefit from higher daily doses, a pain specialist should be consulted. For general advice on other opioids, see the REK list. On the therapy group’s website there is also an updated conversion table.

Risks

Opioids suffer from side effects that need to be followed, as they can be directly harmful or in extreme cases lethal. The sensitivity for opioids varies widely between individuals and, for the most sensitive ones, the dose can easily become too large, especially in the elderly. There is a risk of incorrect doses in drug replacement due to equilibrium differences between the different opioids, which also have different bioavailability. Long-term high dose opioid medication has been shown to be a risk factor for various disorders of the endocrine systems. Depression, increased fatigue, decreased libido and/or breast enlargement may be signs of endocrine disorders. Increased attention to signs of endocrine disorder is recommended at daily doses corresponding to 100 mg morphine equivalents and over 6 months of treatment.

Follow-up

Follow-up treatment should be initiated for the first time after 1-4 weeks and thereafter every 3 months to assess further dosage or discontinuation. In case of re-visitation, together with the patient, the function and/or quality of life should be assessed. The Brief Pain Inventory (BPI) or Pain Disability Index (PDI) can serve as a basis for such discussion. The evaluation will be a balance between the effect and side effects where the patient must be involved in the assessment of the treatment outcome. During treatment, the compliance with the prescribing physician is also evaluated, and low compliance may be a reason not to continue prescribing.

Discontinuation and termination

The following suggestions for the treatment of opioid discontinuation do not apply to patients with underlying psychiatric disease and/or addiction that are deemed to require care in specialist psychiatry. It is the patient’s prescribing physician who is responsible for discontinuation is initiated and implemented, with advice from another specialist, if necessary. When taking care of a patient from another level of care, you also assume responsibility for discontinuation and termination of treatment. Before an opioid discontinuation, one has to decide whether or not there is a dependency situation. The diagnosis of drug dependence is based on a behavioral disorder. Without behavioral disturbance one can hardly speak of addiction. The behavioral disorder is shown by the patient indicating that the medicine has disappeared, prescriptions are prematurely terminated, unintended dose increases, withdrawal behaviors about the medications and several independent prescribers. Tolerance and withdrawal symptoms are very common in depression, but may occur without addiction. During step down, one should rather think in percentages than in milligrams because it is very individual in terms of withdrawal symptoms, etc. It is easier to lower at the beginning of a discontinuation. A step down should be seen as a gear that only goes in one direction. Never return to an earlier higher dose. If the patient experiences a painful decrease, stay on the appropriate dose a little longer than planned. Opioid abstinence is extremely rarely dangerous, but is often experienced as very painful. Untreated opioid abstinence usually take a couple of weeks to disappear with the most prominent symptoms of the first week. Abstinence symptoms such as nausea, diarrhea, muscle pain and myoclonus can be alleviated with clonidine 0.1-0.2 mg orally every six hours (T. Catapres 75 μg, license preparation).

Discontinuation without dependence

The patient usually wants to get rid of the opioids and the important thing is to find a reasonable rate to expel them. This may take from a few weeks to a number of months depending on individual differences, the length of the opioid treatment and the doses that have been relevant. The important thing is that the reduction continues in the right direction. After a long period of opioid treatment, one can often have a reduction rate of about 5-10% per week from the initial dose, a little slower at the end. Shorter postoperative opioid therapy should be staged in a few weeks in a smooth course.

Discontinuation in addiction

Here, the prescriber must take a steady control in the discontinuation, because at best the patient is ambivalent and in the worst case completely reluctant. Fixed clear schedules that apply irrespective of possible patient withdrawal. In a chaotic situation, discontinuation takes place in 3-4 weeks where each date has a dose. If the patient despite his dependence is cooperative and a more stable situation may be slowing down considerably longer. The downturn’s being or not should definitely not be linked to finding “alternative pain relief” as good as you will never find it in such a situation. When the patient has to reduce the dose of the substance they depend on, this will cause strong reactions, no matter who does. Some specialist knowledge is not required in this situation, but may be consulted for advice on further processing if necessary. Non-pharmacological and/or non-opioid treatment can be tested, but if it does not produce the desired effect, there is no reason to interrupt the escalation. For further advice on escalation and release, see FAS UT 3 (www.fasut.nu).

Level of care

Opioids in long-term non-cancer-related pain is expected to be introduced into and out of both the in-house and out patient treatment areas. In case of complicated mental and/or somatic illness, a specialist may need to be consulted.

References

  1. Recommendations of the Medical Products Agency. Use of opioids in non-cancer related pain. In 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. FACE OUT 3.

 


Intrathecal Catherization for Treatment of Pain

Intrathecal pain treatment is applied by placing an epidural catheter under strict sterile conditions in the spinal space via a lumbar puncture with an epidural needle. The catheter is then used for continuous spinal anesthesia via pump – e g Gemstar pump or CAD pump. This puncture is performed as a spinal anesthesia with an epidural needle. Through the epidural needle, the spinal space is first identified with a spinal needle, a “needle-through-needle technique”. Next, an epidural catheter is placed high up about 15 cm above insertion into L2-L3. The catheter may be advantageously tunnelled subcutaneously from the site of insertion to the side of the patient’s truncus. Intrathecal drug is 100-300 times stronger than perorally given.

Contraindications

High intracranial pressure, sepsis, severe coagulation disorder, increased bleeding risk, anticoagulation treatment (Waran®, Plavix®) and infected skin, e g in the event of skin ulcers near the insertion site.

Preoperative blood samples

PK (INR), APTT, platelets, CRP.

Anticoagulation-treated patients

Waran® treatment is dismissed. Operating doctors should report acceptable INR in each case. Patients treated with low molecular weight heparin, eg Fragmin®, should be treated as follows: At Fragmin 5000 E s c, 10 hours should pass before insertion, position adjustment or removal. Subsequent Fragmin® dose is given 2 hours after insertion or removal of the intrathecal catheter. At Klexane® 40 mg s.c. 10 hours should pass before loading, positioning or deletion. Following Klexane dose is given 2 hours after insertion, position adjustment or removal of the intrathecal catheter. Plavix® is ​​exposed 10 days before surgery.

Medicines for intrathecal administration:

  • 95 ml of Bupivacaine (Marcain®) 5 mg/ml are mixed with 5 ml of Morphine 10 mg/ml to a volume of 100 ml.

The concentration of Bupivacaine (Marcain®) is 4.75 mg/ml and the concentration of morphine becomes 0.5 mg/ml. A recommended starting dose is 0.3 ml/h with the ability to provide a bolus dose of 0.2 ml if necessary. Peroperative pain relief usually occurs by the administration of local anesthetic agents with the addition of opiates, usually morphine 0.1 mg, 100 μg. There is a possibility of adding a mixture of opiates and clonidine (Catapresan). Such a mixture is, for example:

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

Safety checks with intrathecal (subarachnoidal) infusion of opiods

After the morphine has been given intratheously, the following controls are performed for 12 hours and after intrathecal fentanyl or sufentanil have been given for 6 hours. 1 time / hour after spinal anesthetic has been given and checked:

  • VAS
  • Sedation Degree
  • Respiratory Rate (if the degree of sedation > 1)
  • Nausea
  • Itching

Hereafter, checks are performed every 4 hours for another 12 hours. Extra control 2 times/hour for 2 hours when adding sedative or respiratory depression medication. CAD for at least 12 hours. Check bladder function after CAD has been removed.