Pain Relief: An art to be perfected in Medicine
Pain is the most common reason for self-medication and entry into the health care system. Pain, acute and chronic, is now appreciated in a biopsychosocial model that acknowledges the biological, psychological and social dimensions of the pain experience. Effective pain relief is considered a human right.
Pain is defined by the International Association for the Study of Pain (IASP) as an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage. Different diseases produce different characteristics of pain. Location, quality & time course of pain reflects important clues on diagnosis of disease.
Acute pain is defined as pain of recent onset and probable limited duration. It usually has an identifiable temporal and causal relationship to injury or disease'. Acute pain is the most common reason why patients seek medical attention. Common reasons for visits to health care professionals include acute pain (e.g., musculoskeletal pain, gastrointestinal pain, chest pain, and headache) and injuries (e.g., fractures, sprains, lacerations).
Chronic pain 'commonly persists beyond the time of healing of an injury and frequently there may not be any clearly identifiable cause'.
The relief of pain is & always has been, one of the primary aims of medicine.
Effective pain relief is considered a human right derived from these principles (National Health & Medical Research Council, Australia 1999):
β’ Unrelieved severe pain has adverse psychological and physiological effects.
β’ Patients should be involved in the assessment and management of their pain.
β’ To be effective, pain treatment should be flexible and tailored to individual needs.
. Pain should be treated early; established, severe pain is more difficult to treat.
β’ It should be possible to reduce pain to a comfortable or tolerable level.
Acute pain was once defined simply in terms of duration. Now it is viewed as a "complex, unpleasant experience with emotional and cognitive, as well as sensory, features that occur in response to tissue trauma."
Conditions
Defining Pain
Specific Disorders
Acute illness
Pain associated with acute illness
Appendicitis, renal colic, Ml
Perioperative (Including Intraoperative)
Drains, Nasogastric tube
Head neck, abdominal surgery
Post traumatic (Major & Minor)
Generalized or regionalized acute pain due to major or minor injury
Motor vehicular, Accident sprain
Burns
Pain due to thermal & Chemical Burns
Fire, chemical exposure
Procedural Obstetrical
Diagnostic & therapeutic procedures
Labour & delivery
BM biopsy, endoscopy, catheter, Circumcision
Vaginal & Cesarean
Relief of pain in acute musculoskeletal disorders & Day Care Surgery
NSAIDS are the commonly used drugs in various musculoskeletal disorders such as bursitis, tenosynovitis, calcific tendonitis, and sprain. They help in relief of acute inflammation associated with acute musculoskeletal disorders. NSAIDS act as symptomatic treatment in the management of acute inflammatory conditions. Few conditions also require surgical therapy. NSAIDS are the commonly used drugs in chronic inflammatory conditions such as rheumatoid arthritis, osteoarthritis, and ankylosing spondylitis.
Day Care Surgery & early recovery
Management of acute post-operative pain remains sub-optimal despite the availability of multiple analgesics and improved pain management strategies with nearly 80% of patients reporting moderate to extreme pain following surgery.
Alleviation of pain and suffering, especially when it occurs as a consequence of treatment, is a priority for all health professionals. Surgical procedures inevitably produce tissue trauma and release potent mediators of inflammation and pain. Today, there is a continued trend to expand the indications for ambulatory surgery. Day case surgery is the admission of selected patients to hospital for a planned surgical procedure, returning home on the same day. "True day surgery" patients are day case patients who require full operating theatre facilities and/or general anaesthetics. Day-case surgery is of great value to patients and the health service. It enables many more patients to be treated properly, and faster than before. Newer, less invasive, operative techniques will allow many more procedures to be carried out, There are many elements to successful day-case surgery. One of key component is the effectiveness of the control of pain after the operation.
With an increasing amount of surgery being performed as day cases, it is important to know which drug should be recommended for post-operative pain relief.
Recent research on postoperative pain management supports a treatment approach known as "multimodal analgesia" or "balanced analgesia." This approach involves the use of more than one method or modality of controlling pain (e.g., drugs from two or more classes, drug plus non-drug treatment) to obtain additive beneficial effects, reduce side effects, or both. These modalities may operate
through different mechanisms or at different sites (i.e., peripheral versus central actions).
Benefits of multimodal analgesia include earlier oral intake, ambulation, and hospital discharge for postoperative patients as well as higher levels of participation in activities necessary for recovery (e.g., physical therapy).67 It also may reduce postoperative morbidity, mortality, and costs.8 Some pain experts advocate revision of traditional postoperative care programs to include accelerated multimodal postoperative recovery programs.9 Additional potential applications of multimodal analgesia include other types of acute, as well as chronic, pain.
Permitting acute pain to become severe?
Acute pain is more difficult to manage if permitted to become severe, so prompt and adequate treatment of acute pain is imperative.
Treatment goals and strategies for acute pain can be summarized as:
Early intervention, with prompt adjustments in the regimen for inadequately controlled pain.
β’ Reduction of pain to acceptable levels.
* Facilitation of recovery from underlying disease or injury. Strategies for acute pain management
Multimodal analgesia
This approach involves the use of more than one method or modality of controlling pain (e.g., drugs from two or more classes, drug plus non-drug treatment) to obtain additive beneficial effects, reduce side effects, or both. May operate through different mechanisms or at different sites (i.e., peripheral versus central actions)
Preemptive analgesia
Preemptive analgesia refers to the administration of one or more analgesic(s) prior to a noxious event (e.g., surgery) in an attempt to prevent peripheral and central sensitization, minimizing post-injury pain
Drug in the hands of clinicians: Do they strike balance of efficacy & safety?
Pharmacologic management is the cornerstone of acute pain management. Multiple factors (e.g., pain intensity, quality, and pattern; patient preferences; drug side effect profiles) influence the selection of medications. Most acute pain is nociceptive and responds to nonopioids and opioids.
In general, mild to moderate somatic pain responds well to oral nonopioids (e.g., acetaminophen, non-steroidal anti-inflammatory drugs [NSAIDs]), topical agents (e.g., local anesthetics), and physical treatments (e.g., rest, ice, compression, elevation). Moderate to moderately severe acute pain is more likely to require opioids.
Opioid analgesics although effective are associated with numerous adverse effects. These include respiratory depression, marked sedative effects contributing to alveolar hypoventilation, sleep disturbances, nausea and vomiting, ileus and urinary retention. Non-selective NSAIDs have a role in post-operative pain management, but concerns about gastrointestinal tolerability, increased bleeding, inhibited wound healing and bone fusion have also limited their use.
Efficacy of Ibuprofen has been shown in relieving post-operative pain following dental surgery(extraction of tooth), episiotomy, tonsillectomy, inguinal hernia repair have been well established.
Ibuprofen at standard doses give analgesia equivalent to that obtained with 10 mg of intramuscular morphine. Ibuprofen will provide at least 50% pain relief from a single oral dose in patients with moderate or severe postoperative pain.
, and easier dose optimization, all at half the dose of ibuprofen. Dexibuprofen is the dextrorotatory (S(+)), active enantiomer of racemic ibuprofen. Racemic ibuprofen consists of equal portions of S(+)-ibuprofen and R(-)-ibuprofen. Dexibuprofen and ibuprofen in a dose ratio of 1:2 have provided comparable analgesic and anti-inflammatory activity in several studies. Potential advantages of dexibuprofen over racemic ibuprofen include lesser toxicity, greater clinical efficacy and/or less variability in therapeutic effects achieved
The analgesic efficacy of paracetamol is essentially equivalent to that of NSAIDs, but acetaminophen is not anti-inflammatory. Paracetamol have a comparably rapid onset of action. Paracetamol is frequently used as a non-opioid analgesic in postoperative pain. Its mechanism of action is not fully understood, but it is generally accepted that paracetamol is a centrally acting drug. The analgesic effect of paracetamol is probably dependent on the rate and amount of active drug reaching the CNS, where its analgesic effect takes place. When pain relief is insufficient with paracetamol alone, an NSAID may be added in combination. NSAIDs inhibit prostaglandin synthesis in peripheral tissues. Some suggest a peripheral- central synergistic action of NSAIDs that varies depending on the particular NSAID and on the presence of an inflammatory process. Concomitant administration of two analgesics with presumably different mechanisms of action may be more effective than the use of either drug alone. In five clinical studies, authors reported significant reductions in opioid consumption, ranging from 33-46%, when NSAIDs & paracetamol were used in combination compared with paracetamol alone.
What does dexibuprofen & paracetamol combination have to offer?
A combination of dexibuprofen and paracetamol needs designing in terms of dosage and formulations. It is initiated to have a well designed formulations to strike balance of efficacy and safety. Given, ibuprofen provides utmost pain relief to its optimum in dosage ranging between 600-800 mg; hence, it becomes essential to select in accordance of the dosage of dexibuprofen i.e. 300 mg which will deliver the task of pain relief. Similarly, to add the analgesic impact of paracetamol, the suitable available option is 500 mg.
Therefore, Sibet P combines the two in relevant strength i. e. Dexibuprofen........................... 300 mg
in soft gelatin capsule, to enhance patient compliance coupled with efficacy.
Clinical Pharmacology Of Dexibuprofen Pharmacotherapeutic group:
Antiinflammatory and antirheumatic products. Propionic acid derivatives.
β’ Ibuprofen) is marketed commercially and used clinically as a racemic mixture of S(+)- and R(-)-enantiomers, which exist in equal amounts
β’ Dexibuprofen is the S(+) (dextrorotatory)-enantiomer of ibuprofen.
β’ Dexibuprofen forms only about one-third of the metabolites formed by racemic ibuprofen
Dexibuprofen is the S(+) (dextrorotatory)-enantiomer of ibuprofen accounts for analgesic, antiinflammatory, antipyretic activities of the racemic compound.
β’ In vivo, the R(-)-enantiomer of racemic ibuprofen undergoes unidirectional enzymatic chiral inversion to S(+)-enantiomer (dexibuprofen). This occurs to the extent about 65%, whereas there is no bioinversion of S(+)- to R(-)-ibuprofen.
β’ In vitro, dexibuprofen is over 100 times as potent as the R(-)-enantiomer as an inhibitor of prostaglandin biosynthesis.
β’ Any observable in vitro effect of R(-)-ibuprofen is secondary to small amounts of dexibuprofen present as an impurity.
Physical properties of Dexibuprofen:
Dexibuprofen and rac-ibuprofen are two inherently different solid-state materials; different in physicochemical properties in the following aspects
. Different crystal binding energy
β’ Different melting points
β’ Different values for the heat of fusion
β’ Solubility twice as high as that of the racemate
β’ Multiplying the dose of racemic ibuprofen by 0.66 to get the dose of dexibuprofen result in equivalent oral absorption
Dexibuprofen and ibuprofen in a dose ratio of 1:2 has comparable analgesic and anti-inflammatory activity
Mechanism of action:
β’ Inhibits prostaglandin synthesis and formation of thromboxanes via blockade of cyclo-oxygenase (COX) enzymes
β’ Inhibits leukotrienes production
β’ Inhibits inflammatory edema by action on polymorphonuclear leukocytes
β’ Reduces sulphated glycosaminoglycan synthesis in articular cartilage in vitro
β’ Inhibits nitric oxide synthesis via inhibition of iNOS induction. Inhibition of prostaglandin biosynthesis by dexibuprofen
The enzyme in prostaglandin synthetic pathway is prostaglandin endoperoxide synthase, or cyclo-oxygenase. This enzyme converts arachidonic acid to PGG2 and PGH2. COX-1 is a constitutive isoform found in normal tissues and isoforms, stomach COX-2 is induced by cytokines and inflammatory mediators, expressed in kidney, brain.
It is also shown that by in vitro study that 100 M of dexibuprofen inhibited the biosynthesis of LTB-4 by approximately 30%. It is suggested that the mechanism of the reduction of LTB-4 production is by the inhibition of 5-lipoxygenase activity. This finding could be one explanation for the favorable balance between therapeutic efficacy and tolerability for dexibuprofen
Pharmakokinetics: Absorption:
Dexibuprofen is absorbed primarily from the small intestine. Bioavailability92%with oral administration. This explains greater clinical efficacy of Dexibuprofen.
Effects of Food:
The administration of dexibuprofen with a meal delays the time to reach maximum, but has no effect on the extent of absorption. Therefore, the drug should preferably be taken after a meal, to minimize gastric irritation.
Onset of action:
In acute painful conditions, such as dental pain, onset of action is 20 minutes, is more rapid than racemic ibuprofen, which makes it an ideal agent for acute inflammatory conditions.
Peak Response occurs in 1 to 3 hours, in acute inflammatory conditions, with duration of action approximately 6 hours.
There is clinical evidence that dexibuprofen provides faster onset and greater analgesia than racemic ibuprofen but without decreased duration of activity or greater incidence of adverse reactions.
In the oral surgery model of dental pain, the relative efficacy of dexibuprofen versus racemic ibuprofen was compared. It was reported that 400 mg of dexibuprofen provided better analgesic efficacy than 400 mg of the racemate. Both drugs were superior to placebo.
Drug Concentration Levels:
There is co-relation between average and trough plasma levels of dexibuprofen. Average and trough levels of S(+)-ibuprofen during every-6-hour dose intervals were 11 mcg/mL
Time to Peak Concentration: Average 2 hours, 2.1 hrs under fasting conditions, & 2.8 hrs under non-fasting conditions.
Following oral doses of 200 and 400 mg dexibuprofen to healthy subjects, peak plasma concentrations were approximately 13mcg/ml_ and 24mcg/mL, respectively.
AUC values (0 to 12 hours) of 49 and 96mcg x hr/mL were calculated following single oral doses of 200 and 400 mg dexibuprofen, respectively, in healthy subjects.
Distribution:
Volume of Distribution 10 to 11 L.
Like all NSAIDS, the plasma protein binding is high, about 99 %.
Maximum plasma levels are reached about 2 hours after oral administration.
Distribution into the cerebrospinal fluid is significant, which increases its efficacy as a good analgesic agent. The CSF half-life was about 8 hours.
Metabolism:
Extensively undergoes metabolism in the liver.
Oxidation and glucuronidation are metabolic pathways. Hydroxylation is mediated in part by cytochrome P450-2C9, which explains the occurrence of drug-drug interactions. Inactive metabolites include dexibuprofen glucuronide, 2-hydroxydexibuprofen, and 3-hydroxydexibuprofen.
No bio-inversion of dexibuprofen to R(-)-ibuprofen occurs in vivo.
Excretion:
Inactive metabolites of dexibuprofen are detected in plasma or urine.
The pharmacologically inactive metabolites are completely excreted, mainly by the kidneys (90%), but also in the bile.
The elimination half-life is 1.8 - 3.5 hours. As the drug has a short half-life of 2 hrs, it exhibits an excellent safety profile.
The graph explains a more rapid Cmax and greater peak concentration of dexibuprofen in comparison with racemic ibuprofen.
Contraindications:
Treatment of peri-operative pain in setting of coronary artery bypass graft (CABG) surgery
Hypersensitivity to dexibuprofen Precautions:
Administered with caution in patients with past history of serious cardiovascular thrombotic events, severe liver dysfunction, severe renal failure.
Patients with active or suspected gastrointestinal ulcer or history of recurrent gastrointestinal ulcer.
No documented studies in pregnancy, to be used with caution in elderly or debilitated patients and in pregnancy.
History of allergic rhinitis or broncial asthma. Adverse reactions:
Cardiovascular adverse events include fluid retention, hypertension, pedal edema. Pre-existing cardiovascular disease or risk factors increase the risk of myocardial infarction and thrombotic events.
Patients may develop serious gastrointestinal adverse effects including ulcerations, bleeding, or perforation, these adverse effects may occur at any time during treatment with orwithout warning symptoms.
Other adverse events include anemia, inhibition of platelet aggregation, skin rashes, scaling eczema, exfoliative dermatitis, drug fever, sometimes anaphylactoid reactions. Some patients can develop vertigo, headache and tremors. There can be borderline elevation in LFTs in up to 15% of patients treated.
Cross-reactivity between aspirin and other non-steroidal anti-inflammatory agents has been reported in aspirin-sensitive patients, which can precipitate Severe bronchospasm. Dexibuprofen may occasionally precipitate acute renal failure in patients and papillary necrosis.
Safety profile:
The factors associated with a variation in the level of risk of gastrointestinal bleeding or ulcer perforation and the extent to which the risk varies between different members of the class of NSAI Ds have also been investigated.
In the last 5 years, 4836 patients have been exposed to dexibuprofen in clinical trials and post-marketing surveillance trials. Out of these, 3.7% of patients experienced 249 adverse events related to dexibuprofen. Moreover, only three serious adverse drug reactions (0.06%) were observed. The majority of adverse events and adverse drug reactions were gastrointestinal, indeed, 80% of the reported adverse events occurred in the first 20 to 40 days of exposure.
Dose of administration:
In the dose ratio of 0.5 :1 (dexibuprofen vs. racemic ibuprofen) atleast equivalent efficacy was shown in acute mild to severe somatic and visceral pain models like lumbar vertebral syndrome, rheumatoid arthritis, distorsion of the ankle joint, ankylosig spondylitis, activated ostheoarthritis of the hip, ostheoarthritis of the knee, postoperative dental pain or dysmenorrhoea.
These effects were provided at daily doses of dexibuprofen ranging from 200 mg to 1800 mg with most at 600 to 1200 mg daily
Advantages of Dexibuprofen over racemic ibuprofen
* Lesser toxicity
Β» Greater clinical efficacy
Β« Less variability in therapeutic effects achieved
β’ Easier dose optimization
* Half the dose of ibuprofen
A more rapid onset of analgesia ,greater peak analgesia
No increased incidence of adverse reaction. Pre clinical efficacy data: Comparison of efficacy of Dexibuprofen and Racemic ibuprofen
The analgesic and anti-inflammatory actions and the related acute mucosal gastric damage from dexibuprofen, was compared with racemic ibuprofen in rodents.
The anti-inflammatory action of the dexibuprofen, assessed with the abdominal constriction test in mice (IV and PO) and with hind paw edema in rats. The anti-nociception was evaluated by hot-plate and tail-flick methods after IV and oral (PO) administration in mice and after PO administration in rats.
Conclusion: S(+)-lbuprofen was at least twice more potent than the ibuprofen racemic formulation.
Dexibuprofen reduces gastric damage and improves analgesic and anti-inflammatory effects in rodents.
Clinical efficacy data:
Gastrointestinal tolerability safety profile:
Study design: Gastrointestinal tolerability test was performed in 41 patients with degenerative rheumatic diseases.
Drug intervention: 200 mg Dexibuprofen TID in 21 patients, SOOmg Dexibuprofen TID in 20 patients, for a period of 14 days.
Changes in gastric mucosa were studied by determination of serum pepsinogen-| and pepsinogen-ll levels.
Results: Increase in pepsinogen-| & pepsinogen-ll levels after 14 days of treatment with dexibuprofen.