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Symptomatic therapy with opioid analgesics

1. Abstract
2. Introduction
3. Pharmacological treatment of rheumatic pain
4. Pain therapy according to the WHO scheme
5. Pharmacological effects of opioid analgesics
6. Opioids in the treatment of rheumatic pain
7. Active ingredients
8. Summary
9. Literature

 

1. ABSTRACT

Treating chronic musculoskeletal pain is often difficult. For this reason, opioids are being used more and more frequently for chronic musculoskeletal complaints and despite little or no evidence for their pain-relieving and function-improving effects. However, their side effects are common and can be serious. Opioid-induced hyperalgesia can lead to an increase in dose and intensification of pain and an increase in the risk of side effects. Long-term treatment of rheumatic pain with opioids should be done with caution.
 


2. INTRODUCTION

Chronic pain disorders of the musculoskeletal system are common. Their treatment is intended to improve the quality of life and to maintain or regain the physical functions of the musculoskeletal system. Treating chronic musculoskeletal pain is often difficult. For this reason, opioids are used more and more frequently and often without criticism.



3. PHARMACOLOGICAL TREATMENT OF RHEUMATOLOGICAL PAIN

The pathogenesis of rheumatic pain can be characterized by inflammatory as well as non-inflammatory processes. The influence of central sensitization processes can contribute to chronic rheumatic pain. Depending on the dominance of the underlying process, either anti-inflammatory or primarily analgesic substances can be indicated in symptomatic treatment.

A medicinal "basic therapy" as a disease-modifying, secondary prophylactically effective treatment has not been available for many musculoskeletal pain conditions. “Peripheral” analgesics and non-steroidal anti-inflammatory drugs (NSAIDs) are used with varying degrees of success. Despite the sparse available data on the symptomatic therapy of rheumatic pain, opioids are used to improve pharmacological pain therapy. Treatment recommendations and guidelines1-6 are mostly based on the WHO pain therapy scheme7developed for oncological patients.



4. WHO SCHEME PAIN THERAPY

Non-opioid analgesics (NOAs) such as paracetamol and non-steroidal anti-inflammatory drugs (NSAIDs) are recommended alongside co-analgesics (antidepressants, anticonvulsants) as “basic therapy” in the WHO tumor pain management scheme7,8. In the case of severe pain, weak opioids (codeine, tramadol, tilidine) are also used, and in the case of insufficient effectiveness the strong opioids (morphine, methadone, hydromorphone, oxycodone, levorphanol, pethidine, fentanyl or buprenorphine) are used in addition to the NOAs . The scheme found its way into general pain therapy in the 1990s without any significant scientific examination. It is considered to be tried and tested and is used as a guide for non-tumor pain therapy7
 


5. PHARMACOLOGICAL EFFECTS OF OPIOID ANAGETICS

Opioids are chemically heterogeneous substances that bind to different opioid receptors in the CNS and in peripheral organs. This explains their analgesic, but also their undesirable effects affecting different organ systems. Immunosuppressive properties of opioids have been tested on animals9 and found in human studies. The clinical relevance has not yet been clarified10.

Abuse has long discredited the entire opioid group. Investigations into mechanisms of action and effects were first carried out with (formerly) opioid addicts. The results of these examinations and the data from the use of opioids in palliative medicine must not be transferred uncritically to other patient groups. The use of opioids in the treatment of acute pain, the treatment of pain in advanced tumor-associated diseases and in acutely life-threatening diseases is undisputed.

The spectrum of side effects known from its use in the seriously ill limits the use of opioid analgesics. The most important adverse effects are sedative or respiratory depressive properties, dizziness (20%), drowsiness (18%), impaired perception, nausea (30%), vomiting (13%), loss of appetite, itching, urinary behavior, orthostatic disorders, constipation (23 %) or fear of developing an ileus11. Central sedative properties and orthostatic disorders result in an increased risk of falls and impaired driving ability. After just one month of use, the potential for side effects can increase due to the development of pharmacological tolerance and opioid-induced hyperalgesia or due to the increased pain caused by the course of the disease with a subsequent increase in dose12. With long-term therapy, depending on the dose, an increase in pain sensitivity with phenomena similar to neuropathy must be expected. Opioids induce hypogonadism with loss of libido, infertility, fatigue, depression, anxiety disorder, loss of muscle mass and strength, osteoporosis and compression fractures in men and women, impotence in men, menstrual disorders and galactorrhea in women13. Because of the complex mechanisms of action, measures against such side effects are often without the desired success14. In many patients, psychological effects are increased during long-term therapy, typical for drugs with a considerable potential for abuse, which manifest themselves as difficulty in stopping the prescribed opioids without a tendency to abuse being recognized. These patients continue the treatment although they do not experience any reduction in pain or an improvement in function15.

Acute opioid intoxication is characterized by the typical triad of coma, miosis and respiratory depression, which is treated by ventilation and administration of an opiate antagonist (e.g. naloxone)16; 43.

After discontinuing therapy, especially with strong opioids, a withdrawal syndrome can occur. Opioids are therefore only indicated in the pain therapy of non-acute rheumatic pain when the therapeutic alternatives have been exhausted.

 


6. OPIOIDS IN THE TREATMENT OF RHEUMATIC PAIN

Weak opioids are used in combination with NOAs according to the WHO scheme. Their usefulness is limited. Ceiling effects or antagonization phenomena make the dose increase in the case of insufficient therapeutic success or the combination with strong opioids pointless (see table). Strong opioids have no pronounced ceiling effect and replace the weak opioids in the third WHO level. The effective dose may be titrated over a period of several days. In chronic pain patients, low doses of strong opioids are often sufficient17. 

Opioids are given at regular intervals at fixed times. Additional single doses may be necessary in case of "breakthrough pain". The oral application of retarded preparations and transdermal systems are preferred to rectal, parenteral or subcutaneous administration because of the lower fluctuation in plasma levels18.

Because of the unacceptable potential for side effects, higher doses should only be used in the case of pain that is otherwise refractory to therapy, with appropriate precautionary measures. In this case, an antiemetic should be comedicated prophylactically and constipation prophylaxis should be used. The therapy should be carried out in a standardized manner. This includes the long-term regular medical monitoring of the patient, including relevant anamnesis and physical examination, careful documentation and the keeping of a pain diary by the patient19.

If the therapy is not successful or if it disappears, the treatment must be ended and other treatment methods sought. After a latency period of a few months, a new attempt at therapy with lower doses can be attempted17.

Osteoarthritis (osteoarthritis, OA)

OA is one of the rheumatic diseases for which several clinical studies with different opioid analgesics have been carried out. The EULAR guidelines and other national and international guidelines recommend the use of opioid analgesics if NSAIDs or paracetamol have not shown a satisfactory effect. However, attention is drawn to the increased risk of undesirable effects, especially in older patients, as well as the potential for dependency2,20,21. In a meta-analysis, opioids showed good pain relief in OA patients. However, they only had a minor impact on function. The median duration of the clinical trials assessed was 4 weeks (1.4-13 weeks). Short-term therapy can be carried out with an acceptable risk of side effects. The clinical data on long-term efficacy and tolerability are insufficient for an assessment. Although they watched

Side effects were reversible, they very often led to discontinuation of therapy (31% for strong opioids and 19% for weak opioids)11. Studies with a sufficient number of patients to allow comparison with NSAIDs are not available.

Ankylosing spondylitis

There is insufficient experience with opioid analgesics in patients with ankylosing spondylitis (AS)22. The ASAS / EULAR guidelines recommend that the use of opioids for pain control be considered in those patients in whom NSAIDs are ineffective, contraindicated or not tolerated22,23.

Rheumatoid arthritis

There is insufficient experience with opioid analgesics in patients with rheumatoid arthritis (RA). In a study of RA patients, two thirds of the patients reported inadequate pain control24. Opioid analgesics have no effect on disease activity and should therefore not replace or delay adequate therapy with DMARDs25. The EULAR has not yet formulated a statement on this26.

Osteoporosis pain

Both chronic back pain in osteoporosis and acute, very severe pain after vertebral body fractures can make the short-term use of opioids necessary if other treatment options fail27. Because of their central sedative effect, opiates are associated with an increased fall and fracture rate. They reduce the release of various hormones such as prolactin, FSH, LH, testosterone and estrogen and thereby increase the risk of osteoporosis13.

Chronic non-specific back pain

Several clinical studies with different opioid analgesics are available for the symptomatic treatment of chronic non-specific back pain28. However, the studies on long-term use do not provide enough meaningful data to be able to derive a recommendation. In comparison with naproxen, no difference in effectiveness was found with a small number of cases. Side effects have been documented more frequently with opioids28.

Fibromyalgia

According to EULAR recommendations, weak opioids such as tramadol could be tried therapeutically29. However, there is not a single double-blind randomized clinical study that investigates a common group of fibromyalgia patients with an opioid analgesic as monotherapy. Due to the known risks (addiction, abuse), the typical symptoms after discontinuation of therapy and the lack of clinical studies, especially on long-term use, therapy with weak opioid analgesics cannot be recommended for fibromyalgia. Strong opioids are not recommended by the EULAR.

 


7. ACTIVE INGREDIENTS: SELECTION, PROPERTIES, DOSAGE

Weak opioids

Weak opioid analgesics are not subject to the Narcotics Ordinance. In the case of chronic pain, only retarded preparations should be used. Opioid analgesics should generally only be used for very severe pain that cannot be adequately treated with other analgesics. Most clinical studies with weak opioid analgesics are available for tramadol.

Tramadol is often accompanied by nausea and vomiting. It is not advisable to increase the dose beyond the recommended daily dose30-34. A meta-analysis comes to the conclusion that tramadol and the combination with paracetamol improve both pain and function, but that this benefit is minor32.

246 OA patients were examined in a 12-week double-blind, randomized, placebo-controlled study. Treatment was started with 100 mg tramadol and increased to 200 mg by the end of the first week. A maximum daily dose of up to 400 mg was allowed. After 12 weeks, tramadol was found to be statistically significantly superior (Arthritis Pain Intensity VAS 30.4 vs 17.7 mm, P <0.001). Significant differences to the placebo group were found after just one week. The most common side effects in the group treated with tramadol were dizziness (33%), nausea (24%), constipation (26%), headache (15%)33.

In another 12-week double-blind, randomized, placebo-controlled study, 1020 OA patients were examined. It was titrated up to different daily doses: 100 mg, 200 mg, 300 mg, 400 mg. After 12 weeks, tramadol was statistically significantly superior to the placebo group from a daily dose of 200 mg (Arthritis Pain Intensity VAS 30.2 vs 20.2 mm). Significant differences to the placebo group were also found after 2 weeks. The most common side effects in the tramadol-treated group were dizziness (28%), nausea (26%), constipation (30%), headache (16%), pruritus (12%) and insomnia (11%). After treatment discontinuation, 4 patients developed withdrawal syndrome.34

In a 4-week double-blind randomized study, 350 OA patients were treated with either 37.5 mg tramadol plus paracetamol or codeine 30 mg plus paracetamol. The results in terms of pain relief were comparable. The onset of action was documented in both groups after 30 minutes, and the improvement in pain lasted for 6 hours. However, significantly more side effects such as somnolence (24% vs 17%) and constipation (21% vs 11%) were found in the codeine-treated group.36

Codeine is mainly used in conjunction with an NSAID or paracetamol. The combination of codeine / diclofenac was tested over 7 days in 238 OA patients. In the combination group, 5.5% more patients showed a 30% reduction in pain intensity on day 1 than in the group treated with diclofenac. This statistically significant result improved to 10.2% by day 6. The adverse drug reactions were significantly higher at 34% versus 19% in the combination group. The drop-out rate due to side effects was also increased in the combination group (5.3% versus 0.9%)36,37.

Tilidine is combined with naloxone, an opiate antagonist, because of its known abuse potential. This combination also reduces constipation while maintaining the analgesic effect.

Strong opioids

If the analgesic effect of the weak opioids is inadequate, the patient is switched to a WHO level 3 retarded preparation. The dose is increased until effective analgesia is achieved. Fixed time intervals for ingestion / application must be observed. A so-called on-demand therapy with strongly changing serum active ingredient concentrations increases the risk of addiction and the risk of withdrawal symptoms. If treatment is to be discontinued, the therapy should be gradually reduced. Clinical studies on the therapy of rheumatic diseases with strong opioid analgesics for the pain treatment of osteoarthritis are predominantly available.

Oxycodone has been shown to be effective in treating severe pain in both knee and hip osteoarthritis. The duration of the controlled studies ranged from 2 weeks to 3 months. Oxycodone was found to be comparable to oxymorphone. Side effects have been reported very frequently, mostly affecting the gastrointestinal tract and the centrally sedating opioid effects. A sustained-release preparation is available in combination with naloxone, which prevents the accompanying opioid-induced constipation38-40.

Morphine is available for oral use. Parenteral applications are indicated for the treatment of severe and severe pain. The intravenous dosage form should only be used if a particularly rapid onset of action is required. The risk of withdrawal symptoms is greater when treatment is stopped suddenly, so the dosage should be gradually reduced when treatment is discontinued. In renal insufficiency, the metabolic products accumulate. Regular and short-term checks are required. It is only indicated for the shortest possible therapeutically necessary period12,41,42.

Buprenorphine has a long duration of action. It is primarily excreted through the liver. It is available as a matrix patch for basic opioid therapy. The dosing interval is up to 7 days43.

Fentanyl is also used as a transdermal therapeutic system for basic opioid therapy41,44. The dosing interval is 3 days. Hydromorphone does not accumulate in renal insufficiency38.

Dosage forms

Transdermal opioid patches are generally suitable for the basic treatment of chronic pain, but not for the treatment of acute pain. Rapidly available dosage forms (e.g.Buccal tablets) are indicated for the treatment of breakthrough pain under opioid basic therapy [current product information]. Application as required is not considered to be indicated for chronic pain, with the exception of the treatment of breakthrough pain16.

 


8. SUMMARY

The use of opioid analgesics in the treatment of acute pain, especially in tumor-associated and acutely life-threatening diseases, is undisputed. In the treatment of chronic pain associated with rheumatic diseases, opioids are used on the basis of EULAR / OARSI / ASAS recommendations for the treatment of the corresponding rheumatic diseases based on the WHO recommendations for tumor pain therapy only secondarily after the failure of the NSAID therapy. There is currently no special EULAR guideline for the treatment of pain in rheumatic diseases with opioids.

The majority of clinical studies were conducted on the treatment of pain in osteoarthritis, most of them for short-term use. Based on the experience available, supported by the data, the German Society for Rheumatology (DGRh) recommends the following therapeutic approach: Opioid analgesics should generally only be used for very severe pain that cannot be adequately treated with other analgesics.

Treatment of acute pain should be started with a non-opioid analgesic such as a non-steroidal anti-inflammatory drug (NSAID) or paracetamol. In principle, in the case of inflammatory rheumatic diseases or osteoporosis, the options of non-opioid analgesic therapy as well as anti-inflammatory and disease-modifying therapy should have been exhausted. Only then can opioids find their indication in pain therapy for chronic rheumatic pain. If the response to NSAIDs is inadequate, a weak opioid can also be used. If the analgesic effect is still insufficient, the weak opioid can be exchanged for a strong opioid analgesic.

In the case of non-opioid analgesic intolerance, opioid analgesics without NSAIDs / paracetamol can be used. Elderly patients or patients in poor general physical condition may experience more severe side effects when using opioids.

It is advisable to exercise caution when prescribing opioids because of the acute and chronic side effects known for opioids (e.g. respiratory depression, constipation). In long-term therapy, opioids can induce pronociceptive mechanisms and exacerbate existing pain. For the treatment of chronic pain, oral opioids should be preferred to parenteral opioids. Therapy has been facilitated by the use of transdermal systems with constant release of active ingredients, as well as combinations of opioids and antagonists. After discontinuing therapy, especially with strong opioids, a withdrawal syndrome can occur.

Table 1: Weakly effective opioids (selection) of WHO level 216,44,45

Active ingredient

Active ingredient group / metabolism

Bioavailability / analgesic potency compared to morphine

Elimination half-life in hours

Dosage single dose (ED) max. Daily dose (TD)

Application type

risk
Codeine

Phenanthrene alkaloid with opiate agonistic properties, partial demethylation to morphine

40%-60%/ 01

3-5 (9-18 for kidney insufficiency)

Codeine Phosphate Hemihydrate
ED: 30-60 mg
TD: 150/240 mg
(depending on the combination partner)

orally, only in combination with non-opioid analgesics

Indication: moderate to severe pain

Morphine intoxication

Dihydrocodeine

Semi-synthetic opium alkaloid, opioid agonist without antagonistic effect, conversion to dihydromorphine in the liver, pronounced first-pass effect

approx. 20% / approx. 0.2

approx. 3-5

Dihydrocodeine [(R, R) -tartrate], ED: 60 mg
TD: 240 mg

orally,

Indication: moderate pain

Highly addictive

Tilidine / naloxone

Prodrug. Oxidative demethylation to the actual active ingredient nortilidine

approx 6% / 0.1-0.2

3-5 (nortilidine)

TD: 100 mg - 600 mg tilidine hydrochloride

orally,

only in combination with naloxone

Indication: severe to very severe pain

Contraindicated in case of hepatic insufficiency. High potential for addiction, risk of acute withdrawal symptoms in opiate addicts

Tramadol

Weak agonist at the μ receptor. Inhibition of norepinephrine uptake and enhancement of serotinin. Release. Demethylation.

60-75% / approx. 0.1-0.2

6

ED: 50 mg
TD: 400 mg tramadol hydrochloride

oral, rectal, solution for injection

Indication: moderate to severe pain

Often nausea, vomiting

In analgesic doses only slight respiratory depression effect


Table 2: Strongly effective opioids (selection) of WHO level 3

Active ingredientActive ingredient group / metabolismBioavailability / relative potency compared to morphineElimination half-life in hours

dosage

Single dose (ED) max.day dose (TD)

Application typerisk
MorphineInteraction with the OP3 (μ) receptor, the metabolite morphine-6-glucuronide also acts as an agonist. Pronounced first pass effect, glucuronidation, excretion mainly renal20%-40%/ 1

1.5-4.5 occasionally up to 9

Adults:

ED (oral): approx. 7.5-75 mg morphine (depending on the preparation, e.g. drops, prolonged-release tablets)

TD (oral): approx. 150-275 mg morphine

D (i.v.): slowly about 3.75-7.5 mg morphine

ED (s.c., i.m.): about 1.9-22.5 mg morphine

TD (i.v, i.m., s.c ..): ED every 4-6 hours if necessary

oral, parenteral (i.v., i.m., s.c.),

available as morphine sulfate and morphine hydrochloride

Indication: severe to severe pain

 

Respiratory depression,

Dependency potential,

Accumulation in renal insufficiency

Hydromorphoneμ-selective opioid agonist. Pronounced first-pass effect, renal excretion of the main inactive metabolite

approx. 32% / 7

approx. 3

ED (oral, retard): 4 mg hydromorphone hydrochloride every 12 hours. This starting dose can be increased gradually if necessary.

ED (parenteral): 1-1.5 mg (IV) or 1-2 mg (s.c.) hydromorphone hydrochloride slowly every 3-4 hours.

oral, parenteral (i.v., s.c.)

Indication: severe to severe pain

Respiratory depression,

Do not give hydromorphone longer than necessary.

OxycodoneOpiate agonist without antagonistic effect.

40-80%/ 2 

4-6

ED (oral, retard): 10 mg oxycodonone hydrochloride every 12 hours. This starting dose can be titrated up in stages if necessary.

TD (oral, retard): 40 mg oxycodonone hydrochloride

ED (oral, acute): 5 mg oxycodonone hydrochloride every 6 hours

ED (parenteral): 1-10 mg (IV) or 5 mg (s.c.) oxycodonone hydrochloride slowly every 4 hours.

oral, parenteral (i.v., s.c., infusion)

Oral also available as a combination with naloxone

Indication: severe to very severe pain

Respiratory depression
BuprenorphinePartial μ antagonist with a long duration of action. Low intrinsic activity, so that the maximum analgesic effect of morphine is not achieved (ceiling effect).

after oral administration only 15%, therefore not suitable for oral administration.

50-55% sublingual / 20th

12-16, terminal elimination phase 20-25

ED (transdermal patch): 35 μg buprenorphine / hour. This starting dose can be titrated up in stages if necessary. Change of patch after 72/96 hours, depending on the preparation. Also available with 5 μg buprenorphine / hour for 7 days.

ED (sublingual): 0.2-0.4 mg buprenorphine every 6-8 hours as needed.

ED (solution for injection): 0.15-0.3 mg buprenorphine every 6-8 hours as needed.

transdermal patch, sublingual, parenteral (i.v., i.m.).

Indication: severe to very severe pain

Respiratory depression (naloxone only effective in high doses, then stimulation of the atremal center with doxapram

Plaster: Increased absorption when the skin is overheated

FentarylPredominantly μ-selective opioid agonist. Metabolized via CYP3A4 in the liver (oxidative N-dealkylation). Renal (75%) excretion of the inactive metabolites.

65% buccal, 30% oral / 800

approx. 3-4 (nasal)

terminal elimination half-life 22 (buccal), 18 (i.v.)

ED (transdermal patch): 37.5 μg fentanyl / hour. This starting dose can be titrated up in stages if necessary. Change of patch after 72 hours.

ED (nasal, for breakthrough pain): 50 μg fentanyl, a second dose after 10 minutes at the earliest. If necessary, titration can be carried out step-by-step up to 2x200 μg.

ED (buccal, for breakthrough pain): 100 μg fentanyl, if necessary, can be titrated up to 800 μg.

transdermal patch, buccal, nasal.

Indication: severe to very severe pain

Respiratory depression

 


9. LITERATURE