Pain is a complex psychobiological process caused by injurious stimuli inside and outside the body, a common clinical symptom of certain diseases, both a physiological type of sensation and an unpleasant emotional activity in psychology, often accompanied by endocrine, metabolic, immune or psycho-psychological changes, how to standardize pain treatment and improve the quality of life is a difficult problem in front of doctors and pharmacists.
1.Definition of pain
According to the definition of pain by the International Association for the Study of Pain (IASP): “an unpleasant sensation and emotional experience triggered by actual or potential tissue damage; or a description of this damage”, pain belongs to an unpleasant physiological experience; it is widely seen in the course of various diseases, and is one of the most common clinical complaints.
2.Orthopedic pain
Orthopedic pain is not an individual disease, but a common and shared symptom of many diseases, and patients often present with complaints. Clinically, pain is divided into acute pain and chronic pain according to different etiology, pathology, duration and treatment principles. For example, acute traumatic pain caused by trauma or surgery is characterized by its rapid onset and intensity.
Therefore, the clinical treatment of pain requires rapid onset, strong anti-inflammatory and analgesic effect, and cannot affect the healing of the wound; while chronic pain such as rheumatoid arthritis and spinal stenosis is characterized by recurrent attacks, long duration, and light and heavy degree, so the clinical treatment requires drugs with long-lasting anti-inflammatory and analgesic effect and good safety.
3.Pharmacological treatment of acute postoperative pain in orthopedics
At present, the important role of postoperative analgesic treatment in improving patient safety, reducing complications and promoting patient recovery has been generally recognized by the majority of experts. In traumatic orthopedic limb surgery, especially microsurgical replantation surgery such as broken fingers and arms, postoperative analgesia can release the spasm of skeletal muscles and tiny arterioles, expand capillaries and improve microcirculation, and also avoid the appearance of hypercoagulation in the body and reduce the chance of venous thrombosis, which is conducive to the success of replantation surgery and patient recovery. Therefore, it is obvious that postoperative analgesia brings many benefits to patients.
Postoperative analgesia has its own special rules. The World Federation of Societies of Anesthesiologists (WFSA) recommends the use of analgesic ladder therapy for the treatment of acute pain, starting with strong analgesic drugs and local blocks for severe pain in the first stage, which can only be administered through the parenteral route because of the severe pain after surgery and the frequent need for postoperative fasting. In the last stage, pain can be controlled with non-opioid drugs such as aspirin.
3.1 Opioids can be administered orally, rectally, transdermally, sublingually, or intramuscularly and intravenously. Intramuscular injection remains a common choice for postoperative analgesia in developing countries. However, the recommended standard dosage is optimal for only a subset of patients, and conservative administration leaves many patients without adequate analgesia. Intramuscular injections are generally considered safe, but the presence of respiratory arrest, respiratory abnormalities, and decreased oxygen saturation may be more severe than other methods of administration. Difficulty in forming stable blood levels, pain at the injection site and slow onset of action are disadvantages of intramuscular injection, especially in pediatric patients. Intravenous injection should be implemented only when resuscitation equipment and personnel are available.
3.2 Non-steroidal anti-inflammatory drugs and other drugs can also be administered by conventional routes. They are mainly used in the later stages of postoperative analgesia to reduce the dosage and side effects of opioids. Clonoxicam (1ornoxicam) is a non-steroidal drug of the xylactam class, which shows equal or even stronger analgesic effects than opioids in various postoperative analgesics. With a short half-life, 1ornoxicam provides rapid and stable analgesia for postoperative analgesia, especially when administered intravenously. In conjunction with completed pharmacodynamic trials, the following dosing regimen is recommended: a loading dose of clonoxicam followed by clonoxicam 0.4 mg-2 ml-1-h-1 continuous intravenous analgesia for 48 h.
3.3 Different postoperative analgesic techniques such as single epidural (EA) analgesia, epidural analgesic pump (PCEA) analgesia, intravenous analgesic pump (PCVA) analgesia, etc. were applied with morphine, fentanyl, levobupivacaine, etc., and satisfactory results were obtained. EA postoperative analgesia has more side effects and shorter analgesic time than PCA pump analgesia, but the cost is lower. The cost is higher. Therefore, the clinical choice of analgesic method should be based on the surgical site, the patient’s physical condition and economic conditions.
Opioid-local anesthetic combination: The combination of epidural local anesthetics and small amounts of opioids can reduce the dose of each drug and the incidence of side effects. Levobupivacaine is the most widely used local anesthetic for postoperative analgesia. Ropivacaine has been increasingly used in postoperative analgesia, and its effects on motor nerves may be milder.
3.4 Local anesthetic techniques. Various local anesthetic techniques are available for postoperative analgesia. Long-acting local anesthetics may produce prolonged analgesia in the postoperative period. Interosseous sulcus brachial plexus block can maintain satisfactory analgesia for 12-24 h. Intercostal nerve block can produce 6-12 h of analgesia after thoracic and upper abdominal surgery. Pleural cavity injection tube placed in the pleural cavity, injecting local anesthetic can produce unilateral thoracic analgesia. Local anesthetic input into the axillary sheath, femoral sheath and sciatic nerve is also used for analgesia and sympathetic nerve block at the relevant parts of surgery.
4.Pharmacological treatment of chronic orthopedic pain
4.1 Definition of chronic pain and chronic orthopedic pain
Moderate or severe persistent pain, which cannot be relieved by itself under certain circumstances and may be accompanied by changes such as depression and anxiety, becomes chronic pain if left untreated. Chronic orthopedic pain includes chronic pain caused by osteoarthritis, rheumatoid arthritis, spinal stenosis, osteoporosis, etc.
4.2 Principles of chronic pain treatment
Patients with chronic pain have reduced quality of life, somatic dysfunction, disability, and are often accompanied by anxiety, depression and even suicide attempts. The aim of treatment is to reduce pain, improve function and improve quality of life. Chronic pain should be treated with a combination of pharmacological and non-pharmacological treatments. Non-pharmacologic treatments include physical therapy (exercise programs), acupuncture, hot and cold therapy, psychotherapy, electrical nerve stimulation of the skin or peripheral nerves, electrical stimulation of the spinal cord or deep brain, nerve block therapy, and nerve destruction. Medications include nonsteroidal anti-inflammatory drugs, opioids, local anesthetics, antidepressants, drugs acting on excitatory amino acid receptors, α2 adrenergic receptor agonists, and hormones.
4.3 Pharmacological treatment of chronic orthopedic pain
4.3.1 Non-steroidal anti-inflammatory drugs (NSAIDs)
In 1991 it was demonstrated that there are two different genetic codes for cyclooxygenase (COX), the genes for COXl and COX2 have been expressed, cloned, isolated and the basic structure clarified separately, with COXl being the structural type and COX2 being the inducible type. It is now believed that COXl is not only a structural enzyme but also an inducible enzyme, which is involved in inflammation and has an exacerbating effect on inflammation, while COX2 is not only an inducible enzyme but also a structural enzyme, such as the presence of COX2 in the kidney, gastrointestinal and brain in the physiological state.
NSAIDs inhibit prostaglandin synthesis, have central and peripheral anti-inflammatory and analgesic effects, and at high doses also inhibit the synthesis of inflammatory mediators such as leukotrienes. COXl inhibitors, which mediate anti-inflammatory, analgesic, and antipyretic effects, also cause gastrointestinal reactions, renal impairment, and inhibition of platelet agglutination; COX2 inhibitors have similar therapeutic effects and inhibit cytokine production.
Recently, it has been shown that the activities of COXl and COX2 overlap to some extent. the gastrointestinal reactions and platelet inhibition of COX2 inhibitors are less severe, but they can still lead to peripheral edema, water and sodium retention, and hypertension. COX2 inhibitors may cause myocardial ischemic complications due to reduced prostacyclin production.
NSAIDs can also be divided into acid and non-acid classes.
Acid NSAIDs are all highly lipid-water polarized, with pKa 3.5-5.5, high protein binding (90-95%+), and doses ranging from a few mg (clonoxicam) to 0.8 g (salicylic acid) with different pharmacokinetic parameters. Acid NSAIDs open the vascular endothelium and have high concentrations in the intestine, kidney and bone marrow, especially in acidic environments (inflammatory tissues, upper gastrointestinal tract, renal collecting ducts), explaining the predominance of adverse effects in the above organs. Chronic inflammation of the upper respiratory tract can lead to drug accumulation in the mucosa and is the cause of aspirin asthma. Acid drugs can be divided into four categories.
(1) low strength, short half-life, such as ibuprofen, for episodic, mild inflammatory pain ;
(2) high-intensity, short half-life, such as diclofenac, clonoxicam, ketorolac, and indomethacin, for acute pain and chronic painful outbreaks of pain. Ketorolac and clonoxicam can be injected ;
(3) medium intensity, medium half-life, such as naproxen;
(4) high-intensity, long half-life, such as ciclosporin. These drugs have high intestinal circulation and a half-life of several days, and are used for chronic pain, but with heavy gastrointestinal adverse effects.
The representative drug of non-acid class is acetaminophen (acetaminophen), pKa is neutral, low plasma protein binding rate, uniform distribution throughout the body, only antipyretic and analgesic effect, few anti-inflammatory effects, low nephrotoxicity, small gastrointestinal adverse reactions, is an important drug for acute and chronic pain treatment. Acetaminophen inhibits peripheral and spinal prostaglandin release and has a certain effect on serotonin which has a spinal analgesic effect. It and other NSAIDs drugs all reduce central nitric oxide (NO) production, but only acetaminophen inhibits COX3 isoenzymes.
Acetaminophen plus NSAIDs exhibit synergistic effects in a variety of animals and humans. Acetaminophen readily crosses the blood-brain barrier, so it has both central and peripheral effects. It has few serious adverse effects, but may lead to hepatotoxicity.
Acetaminophen, clonoxicam, ketorolac, ketoprofen, and diclofenac are among the few NSAIDs currently available for intravenous administration. Acetaminophen can be administered orally, rectally, or intravenously. Dose: 1 g/6h for single-drug analgesia; in hepatic insufficiency or with enzyme P-450-inducing drugs (e.g., anticonvulsants), the dose should not exceed 4 g per day; in combination with NSAIDs the dose should not exceed 4 g per day; rectal administration is slowly and unstably absorbed; the first dose should be no less than 2 g, followed by 1 g/4h.
Acetaminophen (1 g/6h) plus NSAIDs class (e.g., hypromellose 100m g/4h, or ketorolac, ketoprofen, indomethacin, clonoxicam) is recommended after day surgery or small to medium-sized procedures. Both acetaminophen + NSAIDs and acetaminophen + codeine showed faster pain relief, longer duration, and reduced adverse effects, whereas acetaminophen + tramadol showed enhanced analgesia and less significant adverse effect relief.
Recent studies have confirmed the interrelationship between NMDA-NO-COX in pain.PG and NMDA interact in inflammatory injurious pain.NMDA receptors in the spinal cord are activated and PGE2 stimulates the release of NO from the spinal cord.NO reacts with COX and increases enzyme activity, resulting in increased release of PG.COX also decreases tolerance to the anti-injurious effects of morphine. Prolonged application of opioids activates the pain-promoting system NMDA-NO-COX and decreases analgesic efficacy, whereas the combined application of NSAIDs, NMDA-inhibiting drugs and opioids appears to be less tolerant and potentiates analgesic effects.
4.3.2 Opioids
Opioids are used for pain that cannot be controlled by non-opioid medications. It is now advocated that opioids are also used in the early stages of moderate to severe pain. Opioids have different receptor agonistic effects and affinities, with the mu receptor being the most relevant to pain and having no capping effect. Although opioid tolerance can occur in patients with chronic pain, opioid addiction rarely occurs.
4.3.2.1 Classification of opioids Opioids are classified according to strength as weak opioids (unsaturated binding to receptors) and strong opioids, and according to the type of receptor action as agonists, partial agonists, agonist antagonists, and antagonists. Recent studies have shown that strong opioids used in chronic non-cancer pain can reduce pain and improve function without producing rapid tolerance or psychiatric dependence. China’s guidelines for the use of opioids in the treatment of non-cancer pain state that the indications are: moderate to severe pain; non-cancer pain with a clear diagnosis, with particular attention to identifying the pathological cause of pain and whether the pain is injurious or neurogenic; age ≥ 40 years; and the need for treatment with strong opioids when NSAIDs and weak opioids are ineffective or when combined treatments such as physical therapy have failed. Patients should be assessed for their physical and psychological condition before medication administration, and patients must sign an informed consent form.
Opioids have common therapeutic effects and adverse reactions, including analgesia, sedation, pupil constriction, respiratory depression, nausea and vomiting, constipation, pruritus, urinary retention, sweating, tolerance, somatic dependence, and psychiatric dependence. All adverse reactions were tolerated within 1 to 2 weeks, except for constipation, which was intolerable for life, and pupil constriction, which was intolerable for a longer period of time.
4.3.2.3 Treatment of major adverse reactions.
(1) Nausea and vomiting: Short-term tolerated adverse reactions. The first-line treatment drug is gastrofacial l0mg, 3 to 4 times/day, but it is less effective for nausea and vomiting caused by drugs such as tramadol. Other first-line antiemetic drugs: haloperidol 5mg per day, but also reported 2.5-5mg per day can cause extrapyramidal symptoms; the role of 5-HT: receptors of the drug Endanserone 8mg, 2-3 times / day or Glasgene 3mg per day, etc.; dexamethasone has good antiemetic and synergistic effect with other antiemetic drugs, 5-l0mg, l-2 times / day. Chlorpromazine 5 to l0mg each time, slow sedation, antiemetic effect is good, but the defect is that it may lead to hypotension and excessive sedation.
(2) Respiratory depression: Strong stimulation and pain are stimulants of respiratory depression. In severe cases, naloxone can be used 0.1-0.2mg each time to restore breathing to more than 8 times/min. If ineffective, the dose should be multiplied until 2.0mg, and the drug should be repeated for 4-6h.
(3) Sedation and drowsiness: excessive sedation, if brain disease or other causes of dysfunction are excluded, suggests drug overdose. Mild sedation can use caffeine, dextroamphetamine, methylphenidate and other central excitatory drugs.
(4) Constipation: It is a stubborn complication of opioids, and treatment includes increased fiber and other foods that promote bowel movement, senna, fruit guide, magnesium sulfate, mannitol and other laxative drugs, and oral naloxone or norethindrone. Since constipation is both related to the central action of opioids and depends on their concentration in the gastrointestinal tract, its incidence is significantly lower with non-oral preparations (e.g., fentanyl transdermal patches).
Fentanyl is a synthetic opioid with 70 to l00 times the analgesic strength of morphine. It has low molecular weight (334), high lipid solubility (lipid-water distribution coefficient 814), water solubility, no skin irritation and skin metabolism, and complete transdermal absorption. High plasma protein binding (84% compared to 40% for morphine) and large tissue distribution volume (200 L). Doregis is a transdermal fentanyl delivery system and is a better choice for chronic moderate to severe pain. Fentanyl transdermal patches readily cross the blood-brain barrier without gastrointestinal or hepatic first-pass effects, resulting in strong analgesic effects and low gastrointestinal adverse effects. The metabolites are not pharmacologically active and can be used in patients with hepatic and renal dysfunction. It rarely produces histamine release, and its incidence of bradycardia is low and not clinically significant.
4.3.3 Other analgesic drugs
4.3.3.1 Antidepressants: antidepressants can be used for low back pain and arthralgia, etc. They are as effective for persistent progressive pain, tearing pain and nociceptive hypersensitivity, but pain can rarely be completely eliminated, and stronger adverse effects are their main defects. Analgesic effects are related to sedation, anxiolysis, muscle relaxation, and sleep restoration.
4.3.3.2 Anti-anxiety drugs: diazepam, sulezapine, clonidine, etc. bind to the brain limbic system, open chloride channels, agonize GABA receptors, play sedative, hypnotic, anti-anxiety, muscle relaxation, anticonvulsant effect. Depending on the dose, the effects are anxiolytic-amnesic-sedative-hypnotic in order.
4.3.3.3 Tramadol: a weak opioid receptor agonist, with an affinity for mu receptors of l/6000 for morphine, while inhibiting the release and reabsorption of central 5-hydroxytryptamine and norepinephrine, and enhancing central inhibition of pain downstream transmission. The two mechanisms add up to a monoamine-derived effect antagonizing μ-receptor respiratory depression, but respiratory depression should still be guarded in patients with renal failure. Low tolerance, low dependence, low plasma protein binding (20%), minimal cardiovascular depression, no sphincter effect, no constipation or urinary retention, and no biliary or pancreatic spasm. The main adverse effect is nausea and vomiting, but if you start with a small dose (25mg, 2 times/day) and gradually increase the dose, the maximum amount of not more than 400mg per day, can significantly reduce nausea, vomiting, headache, sleepiness and other adverse effects.
4.3.3.4 Ketamine: The mechanism of action includes non-competitive binding to NMDA receptors, opioid receptor effects, nicotinic and toxopamine effects. Nerve and soft tissue injury causing pain can lead to central nerve sensitization, in part through excitatory amino acid (NMDA) receptor agonism. The only seven NMDA receptor antagonists now available are the four NMDA receptor antagonists azamethonium, amantadine, dextropropoxyphene, memantine, and the three opioids methandienone, dextropropoxyphene ( dextropropoxyphene) and ketobemidone.
Small doses of azamethonium (1-2 μg-kg-1-min-1) combined with morphine sedation have a synergistic effect on postoperative orthopedic pain, and small doses of ketamine combined with strong opioids or local anesthetics used systemically or in the spinal canal have an over-the-top analgesic effect. The analgesic effect is particularly good in those with peripheral nerve compression and injury.
Studies have shown that competitive and non-competitive NMDA receptor antagonists can inhibit the development of opioid tolerance. The non-competitive NMDA receptor antagonist MK-801 reduces opioid tolerance and dependence without affecting the anti-injurious effects of opioids.
There is a positive feedback mechanism between opioids and excitatory amino acids, especially NMDA receptors, and intracity injection of a small dose of azadirachtin (1 mg) enhances the analgesic effect of morphine in experimental animals.
Opioid tolerance is often accompanied by down-regulation of opioid receptor function and NMDA receptor activation.
4.3.3.5 α2-adrenergic receptor agonists: α2 receptor activation inhibits central and peripheral norepinephrine release, decreases injurious conduction, and regulates body temperature and motor behavior. Colistin has been widely used for acute and chronic pain treatment by oral, intramuscular, or intralesional injection, and has analgesic synergistic effects with local anesthetics and opioids in both central and peripheral areas, and for opioid-tolerant chronic pain, it also has It also has analgesic effects on opioid-tolerant chronic pain.
4.3.3.6 Calcitonin: It has significant analgesic effects, and the mechanism of action is not well understood, but may be related to the regulation of the downstream pain sensory control pathway. Calcitonin is not only used for the treatment of osteoporosis, but also has good effect on phantom limb pain and even complex regional pain syndrome (CRPS).
4.3.3.7 Hormones
The analgesic effect of hormones has not been confirmed, and there are still different views on their application as analgesic purpose, so the indications and contraindications should be strictly controlled. The indications for hormones include cancer pain, especially bone metastatic pain and pain caused by inflammatory reactions in certain acute bones and joints, muscles, ligaments and myofascia. Contraindications include osteoporosis, fracture trauma repair period, diabetes, hypertension, active peptic ulcer, infectious diseases, etc.
The combination or overlapping of drugs of the same nature only increases the dosage of drugs, which does not improve the efficacy, but increases the incidence of adverse reactions.
Single drug analgesia and simple analgesia are sometimes difficult to achieve the desired therapeutic effect, and can be used in combination according to the actual situation of the patient and active causal treatment to increase the efficacy and reduce adverse reactions. Some scholars believe that the management of orthopedic pain is a kind of symptomatic treatment, which is suspected of masking the disease and delaying treatment.
However, the current more consistent view is that after a clear diagnosis or during the treatment process, reasonable analgesic drugs chosen according to the patient’s condition can relieve the pain of the patient’s organism, reduce the patient’s mental pressure, help improve the patient’s quality of life, and complement the smooth progress of etiological treatment. In conclusion. Only by carefully analyzing the causes of pain and the advantages and disadvantages of various pain treatments can orthopedic pain be treated safely and effectively.