Medical Academy Journal (2022) 1: 6-13

https://doi.org/10.56823/OLPU5844

Pain: the use of paracetamol in multimorbid patients

Francesco Salamone

Azienda Sanitaria Provinciale di Palermo, Palermo, Italia/ General Pratictioner

Received: October 28th, 2022

Accepted: November 7th, 2022

Published online: November 14th, 2022

© The Author(s) 2022

Corresponding author: Francesco Salamone

Azienda Sanitaria Provinciale di Palermo, Palermo, Italia/ General Pratictioner

Cortile Cattedrale 6, 90040 San Giuseppe Jato (PA) Italia.

e-mail: francosal@libero.it

abstract

Introduction: More than one third of Italians have at least 2 chronic comorbidities, and this percentage is more than 50% after the age of 75 years. The presence of comorbidities has as a consequence politreatments, with a high probability of drug interactions and adverse events.

Methods: Medical literature about physiopathology of pain and its treatments was reviewed and combined with expert opinion of the authors.

Results: Pain is “An unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage”. Chronic pain is one of the main factors that impact on quality of life and is the leading reason why patients seek medical care.

Pain can represent a defense against potential or real damage to the body, but chronic pain becomes a disease itself, with a profound negative impact on quality of life. Paracetamol is a drug with analgesic and antipyretic action widely used both alone and in combination with other medications. It is an effective and safe drug, and can be used in infants and elderly, in patients in whom NSAIDs are contraindicated, in pregnant or breastfeeding women. A large number of studies have recognized the efficacy and safety of paracetamol in treating pain, and the drug is included in the WHO’s List of Essential Medicines. EULAR, AAOS and NICE guidelines recommend paracetamol as the first-choice analgesic in several conditions like osteoarthritis or post-surgical pain.

Conclusions: Paracetamol, due to its efficacy, safety of use, poor interaction with other drugs, appears to be the first-choice treatment of painful syndromes in the elderly patient.

Keywords: Pain treatment, paracetamol, elderly

Introduction

Health in Elderly

According to the 2015 ISTAT report, life expectancy in Italy is considerable for citizens aged 65, (18.9 for men and 22.2 for women), one year higher than the average for other European countries; however, elderly people have the lowest health-related quality of life1; in the age group between 65 and 69, 37.6% of Italians have at least 2 chronic comorbidities, a percentage that exceeds 50% in the age group of 75-79 years, with severe motor limitations in over 20% of cases1.

Chronic pain, mainly caused by musculoskeletal pathologies such as osteoarthritis, lumbar and cervical pathologies, is one of the main factors that impact on quality of life1.

The 2019 ISTAT reports a slightly improved situation, with a life expectancy at 65 years of 19.4 years in men and 22.4 years in women, and with an incidence of serious chronic diseases in 46% of men and 41.1% of women over 75 (Fig. 1)2.

The presence of multiple comorbidities involves, among others, the problem of multiple treatments, with a high probability of drug interactions and adverse events3. A study conducted in Germany on 355 patients aged> 65 years with chronic pain has been recently published; the study was aimed at evaluating the frequency of multiple comorbidities (presence of ≥ 2 concomitant diseases), of politherapy treatments, defined as the simultaneous prescription of ≥ 5 drugs, and the onset of possible drug interactions. The results show that more than half of the patients (55.4%) had comorbidities treated with an average of 9 drugs, and in 89.5% of cases the treatment consisted of ≥ 5 drugs (Fig. 2). The authors identified 184 possible interactions in 34% of cases4.

A Spanish longitudinal study of 723,016 multimorbid, elderly patients (65–99 years) followed from 2012 to 2016, reported a significant increase over the years of patients with at least one Medication Related Problems (MRPs) (2012: 66.9% ; 2016: 75.5%); MRPs are independently associated with mortality, duplicated therapy and interaction5. Zerah et coll. in a study on 1,959 hospitalized elderly patients (mean age 79 years) found that more than half had at least one drug-drug interaction, and this percentage was 57% after 12 months6.

In elderly, the incidence of adverse events is higher due to multiple comorbidities and politreatments, and this evidence should be considered with caution when introducing a new drug into the treatment of this type of patients7.

Methods

Pain: definition, physiopathology, transmission and psychological aspects

According to International Association of Study of Pain (IASP) definition, pain is “An unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage”8.

Pain is a complex sensation linked by the transmission of the painful stimulus from the involved tissues to the brain (nociception); the painful stimulus causes unpleasant sensations that depend not only on its intensity, but also on the modalities in which the patient subjectively perceives and experiences the sensation of pain (pain threshold)9,10.

Pain can represent an acute physiological mechanism, a defense against potential or real damage to the body; it is the way by which the Central Nervous System (CNS) is alerted and can avoid or limit the tissue damage9.

Acute pain results from activation of specific peripheral pain receptors (nociceptors) and their type A delta and C nerve fibers, which enter the spinal cord at the dorsal root ganglia and release chemical transmitters which activate the second-order pain-transmission neurons located in the gray matter11. From here they run in the lateral columns until they reach the thalamus and then the cerebral cortex (spinothalamic pathway)11,12 (Fig 3).

Acute pain is often associated with anxiety and sympathetic nervous system overactivity (e.g., tachycardia, increased respiratory activity and blood pressure, pupillary dilation). Since the pain changes from acute to chronic it becomes a disease in itself. Chronic pain is related to continuous tissue damage, and is caused by persistent activation of the fibers. It can also result from persistent damage or dysfunction of the peripheral or CNS (neuropathic pain). Chronic pain is generally associated with mood depression and anxiety, and with signs such as fatigue, anorexia, reduced recreational activities and social relationships, with a profound negative impact on quality of life (Fig. 4). Pain, in particular chronic pain, is the leading reason why patients seek medical care, and represents a disabling and burdensome condition9,13.

Pharmacological treatment of pain: paracetamol

Many classes of drugs are now available for the treatment of pain, with different route of administration and delivery systems. Among them, the most used are non-steroidal anti- inflammatory drugs (NSAIDs), muscle relaxants, antiepileptic drugs, antidepressants, opioids, and local anesthetics7.

Paracetamol (or acetaminophen, N-acetyl-para-aminophenol) is a drug with analgesic and antipyretic action widely used both alone and in combination with other medications, for fever due to cold or flu, or for the treatment of acute and chronic pain. It is a safe drug, and can be used, at the proper dosages, in very delicate population groups such as infants and the elderly, such as in patients in whom NSAIDs are contraindicated, i.e. those with gastric ulcers and bronchial asthma, or pregnant and breastfeeding women14.

Paracetamol has a lower analgesic action than NSAIDs but is often preferred due to its better tolerability. The mechanism of action of paracetamol is not fully understood, but it is now generally accepted that it inhibits the formation of a phenoxyl radical formation from a critical tyrosine residue, essential for cyclooxygenase activity of COX-2, and consequently the PGs synthesis, powerful sensitizers of nociceptive transmission15. Compared with other NSAIDs, paracetamol has a similar antipyretic and analgesic, but not antinflammatory, action, because its activity is inhibited by a high arachidonic acid concentration, present in inflamed tissues16.

When arachidonic acid levels are low, paracetamol is able to inhibit COX-2: this condition occurs in the small hypothalamic vessels (paracetamol easily crosses the blood-brain barrier, reaching the CNS)16 during the febrile response, which paracetamol is therefore able to effectively counteract17. The analgesic effects of paracetamol are mainly expressed through some of its metabolites, in particular AM404, which is formed in the spinal cord and in some supraspinal and cerebral areas; AM404 inhibits the reuptake of anandamide, the main endogenous cannabinoid, inducing analgesia (Fig. 5)14,18,19.

Paracetamol is water-soluble and after oral administration is rapidly absorbed in the first part of the small intestine with a high bioavailability (70 to 90%). It is also well absorbed by the rectal mucosa. Its maximum plasmatic concentration is reached in about 30-60 minutes; Its distribution is fast and uniform in most tissues and fluids with a distribution volume of approximately 0.9 l / kg. The drug is mainly metabolized by the liver and 85-95% excreted in the urine within 24 hours, mainly as sulphate and glucuronate; in the course of hepatic metabolism a small amount of the drug is converted into a highly reactive alkylating metabolite, inactivated by reduced glutathione (Fig. 6). Overdose of paracetamol causes glutathione depletion, with possible acute liver necrosis, which can be prevented by early administration of methionine and N-acetylcysteine. The plasma half-life ranges from 1.9 to 2.5 hours and the total body clearance from 4.5 to 5.5 ml / kg / min20.

At recommended doses, few clinically significant drugs interactions have been documented between paracetamol and other medications. There is considerable controversy over the possible increase in the anticoagulant effect of warfarin, but no serious adverse events have been confirmed in humans at therapeutic doses. Since the absorption of paracetamol is dependent on the gastric content, drugs that alter gastric emptying can modify its pharmacokinetics; but this would not cause serious negative effects21,22. Paracetamol has no effect with the antithrombotic action of salicylic acid23. At normal dosages no evidence of a higher incidence of hepatotoxicity has been found in older subjects, and for this reason it is the most commonly used analgesic in the aged patients24,25.

Discussion

Paracetamol has an effective analgesic action with a high therapeutic index in postoperative and inflammatory pain, with no known abuse potential17,26-28. It is the most widely used pain reliever in the United States, where it is taken by about 50 million Americans every week29. A large number of studies have recognized the efficacy and safety of paracetamol in treating pain, and the drug is included in the WHO’s List of Essential Medicines. In particular, it is present in the list of treatments for pain and palliative care, and among drugs for the treatment of acute attack of migraine30. For the management of patients with mild to moderate osteoarticular pain, paracetamol should be considered the analgesic of first choice17,31-33. For its efficacy and safety, the use of paracetamol is recommended by the European Alliance of Associations for Rheumatology (EULAR) guidelines at doses up to 4 g / day as the first-choice oral analgesic in several conditions, like osteoarthritis of hip and knee31,32 and psoriatic arthritis33. The American Academy of Orthopedic Surgery (AAOS) guidelines recommend paracetamol for post-surgical pain management34; the National Institute for Health and Care Excellence (NICE) guidelines also include paracetamol for various indications, such as osteoarthritis35, hip fractures36, non-complex fractures37, perioperative pain38 and others. Moreover, paracetamol has been shown to be highly effective, safe and well tolerated in the treatment of pain, functional disability, photophobia and phonophobia in the treatment of acute migraine attack27,39,40. The analgesic efficacy of paracetamol in the treatment of mild to moderate acute pain is dose dependent, and the dosage of 1000 mg shows a higher effect than lower dosages, as reported by Gault in a review of comparative trials41 (Fig. 7).

Paracetamol has different and complementary mechanisms of action compared to other analgesic drugs: this justify its use in combination therapies with opiates (codeine, tramadol and oxycodone) and NSAIDs (ibuprofen)16.

Conclusions

The care of elderly patients with co-morbidities and in polytherapy is a problem that health systems will have to deal with more and more frequently. In daily clinical practice, a “disease oriented” approach is still too often adopted for all patients, but it is appropriate when the patients have a single predominant disease, as occurs in clinical trials, to obtain a specific outcome like a survival increase or a stroke prevention. This approach is unsuitable, however, in elderly people, who are almost always affected by multiple, chronic pathologies and treated with multiple therapies, because inevitably brings to a fragmentation of care. A patient oriented system implies that the patient as a whole is the main driver of therapeutic choices, and that the outcomes include not only efficacy, but also the maintenance of safety, with an improvement in the quality of life. This approach minimizes the risk of pharmacological interferences and ADRs (adverse reactions), largely documented scientific literature.

The progressive aging of the population is frequently characterized by the presence of painful pathologies mostly caused by osteoarticular problems, with limitations in functional autonomy, and disability that significantly affects the quality of life. The choice of drugs to be used in pain therapy for the treatment of multimorbid elderly cannot ignore this and must be periodically re-evaluated in order to verify that the therapeutic objectives are achieved while maintaining safety. Paracetamol, acting on pain with multiple mechanisms, may be used either alone, or in synergy with other medications (NSAIDs, opioids) and thanks to its efficacy, safety of use and poor drug interaction, it can represent the first choice for painful syndromes in the elderly patient, as underlined by various guidelines that drive the treatment of this type of pathology.

REFERENCES

  1. ISTAT Report Anno 2015. Anziani: le condizioni di salute in Italia e nell’Unione Europea. 26/9/2017. Available from https://www.istat.it/it/archivio/203820
  2. ISTAT Report Anno 2019. Le condizioni di salute della popolazione anziana in Italia. 14/7/2021. Available from https://www.istat.it/it/files/2021/07/Report-anziani-2019.pdf
  3. AIFA. Pazienti con multimorbilità, la gestione della politerapia e i rischi delle interazioni farmacologiche. 8/4/2015. Available from https://www.aifa.gov.it/-/pazienti-con-multimorbilita-la-gestione-della-politerapia-e-i-rischi-delle-interazioni-farmacologiche
  4. Schneider J, Algharably EAE, Budnick A, Wenzel A, Dräger D, Kreutz R. High Prevalence of Multimorbidity and Polypharmacy in Elderly Patients With Chronic Pain Receiving Home Care are Associated With Multiple Medication-Related Problems. Front Pharmacol. 2021 Jun 8;12:686990
  5. Troncoso-Mariño A, Roso-Llorach A, López-Jiménez T, Villen N, Amado-Guirado E, Fernández-Bertolin S et al. Medication-Related Problems in Older People with Multimorbidity in Catalonia: A Real-World Data Study with 5 Years’ Follow-Up. J Clin Med. 2021 Feb 11;10(4):709
  6. Zerah L, Henrard S, Wilting I, O’Mahony D, Rodondi N, Dalleur O et al. Prevalence of drug-drug interactions in older people before and after hospital admission: analysis from the OPERAM trial. BMC Geriatr. 2021; 21:571
  7. Schofield P, Dunham M, Martin D, Bellamy G, Francis SA, Sookhoo D et al. Evidence-based clinical practice guidelines on the management of pain in older people – a summary report. British Journal of Pain. 2022; 16(1): 6-13
  8. Raja SN, Carr DB, Cohen M, Finnerup NB, Flor H, Gibson S et al. The Revised IASP definition of pain: concepts, challenges, and compromises. Pain. 2020 September 01; 161(9): 1976-1982
  9. Institute of Medicine (US) Committee on Pain, Disability, and Chronic Illness Behavior. Anatomy and Physiology of Pain. In: Osterweis M, Kleinman A, Mechanic D (Eds), Pain and Disability: Clinical, Behavioral, and Public Policy Perspectives; National Academies Press, Washington (DC) 1987:123-145
  10. Scienze motorie: Il dolore. 18/5/2016. Available from https://www.scienzemotorie.com/dolore-definizione-classificazione-e-aspetti-psicologici
  11. Willis WD. The pain system. The neural basis of nociceptive transmission in the mammalian nervous system. Pain Headache. 1985;8:1-346
  12. Kenshalo DR, Giesler GJ, Leonard RB, and Willis WD. Responses of neurons in primate ventral posterior lateral nucleus to noxious stimula. Journal of Neurophysiology. 1980;43:1594-1614
  13. Watson JC. Panoramica sul dolore. Updated March 2022. MDS manual. Available from https://www.msdmanuals.com/it-it/professionale/malattie-neurologiche/dolore/panoramica-sul-dolore
  14. Ohashi N and Kohno T. Analgesic Effect of Acetaminophen: A Review of Known and Novel Mechanisms of Action. Front Pharmacol. 2020; 11:580289
  15. Graham GG, Davies MJ, Day RO, Mohamudally A, Scott KF. The modern pharmacology of paracetamol: therapeutic actions, mechanism of action, metabolism, toxicity and recent pharmacological findings. Inflammopharmacol. 2013; 21:201-232
  16. Bonezzi C, Lora Aprile P, Fornasari D. Terapia farmacologica combinata del dolore: l’asso nella manica del medico di medicina generale. Rivista Società Italiana di Medicina Generale. 2017; 6(24): 25-32
  17. Magni A, Fornasari D, Lapi F, Lora Aprile P. Paracetamolo e osteoartrosi: “facciamo il punto”. Rivista Società Italiana di Medicina Generale. 2017; 5(24):48-51
  18. Anderson BJ. Paracetamol (Acetaminophen): mechanisms of action. Paediatr Anaesth 2008;18:915-21
  19. Beltramo M, Stella N, Calignano A, et al. Functional role of high-affinity anandamide transport, as revealed by selective inhibition. Science 1997;277:1094-7
  20. Paracetamol SmPC
  21. Toes MJ, Jones AL, Prescott L. Drug interactions with paracetamol Am J Ther. 2005 Jan-Feb;12(1):56-66
  22. Kaas Oldenburg LI, Dalhoff KP, Sandoval LØ, and Vermehren C. The Risk of Drug-Drug Interactions with Paracetamol in a Population of Hospitalized Geriatric Patients. Journal of Pharmaceutics. 2020, Article ID 1354209, 9 pages
  23. Saxena A, Balaramnavar VM, Hohlfeld T, Saxena AK. Drug/drug interaction of common NSAIDs with antiplatelet effect of aspirin in human platelets. Eur J Pharmacol. 2013;721:215-24
  24. Mian P, Allegaert K, Spriet I, Tibboel D, Petrovic M. Paracetamol in Older People: Towards Evidence‐Based Dosing? Drugs & Aging (2018) 35:603-624
  25. Jahr JS, Breitmeyer JB, Pan C, Royal MA, Ang RY. Safety and Efficacy of Intravenous Acetaminophen in the Elderly After Major Orthopedic Surgery. Am J Ther. 2012 March; 19(2): 66-75
  26. Hoshijima H, Hunt M, Nagasaka H, Yaksh T. Systematic Review of Systemic and Neuraxial Effects of Acetaminophen in Preclinical Models of Nociceptive Processing. J Pain Res. 2021; 14:3521-3552
  27. Lipton RB, Baggish JS, Stewart W, Codispoti JR, Fu M. Efficacy and Safety of Acetaminophen in the Treatment of Migraine. Results of a Randomized, Double-blind, Placebo-Controlled, Population-Based Study. J Pain Res. 2021:14 3521-3552
  28. Sinatra RS, Jahr JS, Reynolds LW, Viscusi ER, Groudine SB, Payen-Champenois C. Efficacy and Safety of Single and Repeated Administration of 1 Gram Intravenous Acetaminophen Injection (Paracetamol) for Pain Management after Major Orthopedic Surgery. Anesthesiology 2005; 102:822-31
  29. Durso GRO, Luttrell A, and Way BM. Over-the-Counter Relief From Pains and Pleasures Alike: Acetaminophen Blunts Evaluation Sensitivity to Both Negative and Positive Stimuli. Psychol Sci. 2015 June ; 26(6): 750-758
  30. WHO model list of essential medicines, 20th list (March 2017, amended August 2017)
  31. Jordan KM, Arden NK, Doherty M, Bannwarth B, Bijlsma JW, Dieppe P, et al. EULAR Recommendations 2003: an evidence based approach to the management of knee osteoarthritis: Report of a Task Force of the Standing Committee for International Clinical Studies Including Therapeutic Trials (ESCISIT). Annals of the Rheumatic Diseases. 2003;62(12):1145-55.
  32. Geenen R, Overman CL, Christensen R, Åsenlöf P, Capela S, Huisinga KL et al. EULAR recommendations for the health professional’s approach to pain management in inflammatory arthritis and osteoarthritis. Ann Rheum Dis 2018;77:797-807
  33. Gossec L, Baraliakos X, Kerschbaumer A, de Wit M, McInnes I, Dougados M et al. EULAR recommendations for the management of psoriatic arthritis with pharmacological therapies: 2019 update. Ann Rheum Dis 2020;79:700-712
  34. American Academy of Orthopaedic Surgeons/Major Extremity Trauma and Rehabilitation Consortium. Clinical Practice Guideline for Pharmacologic, Physical, and Cognitive Pain Alleviation for Musculoskeletal Extremity/Pelvis Surgery. Published July 19, 2021. Available from https://www.aaos.org/painalleviationcpg
  35. NICE 2022: Osteoarthritis care and management. Updated 11 Dec 2020. https://www.nice.org.uk/guidance/cg177/chapter/Recommendations#pharmacological-management
  36. NICE 2022: Guidelines on Hip fracture: management. Updated 10 May 2017. Available from https://www.nice.org.uk/guidance/cg124/chapter/Recommendations#analgesia
  37. NICE 2022: Guidelines on fractures (non-complex): assessment and management. Published: 17 February 2016. Available from https://www.nice.org.uk/guidance/ng38/chapter/Recommendations#initial-pain-management-and-immobilisation
  38. NICE 2022: Perioperative care in adults. Published 19 August 2020. https://www.nice.org.uk/guidance/ng180/chapter/Recommendations#managing-pain
  39. Derry S, Moore RA. Paracetamol (acetaminophen) with or without an antiemetic for acute migraine headaches in adults. Cochrane Database of Systematic Reviews 2013, Issue 4. Art. No.: CD008040
  40. Peck J, Urits I, Zeien J, Hoebee S, Mousa M, Alattar H et al. A Comprehensive Review of Over-the-counter Treatment for Chronic Migraine Headaches. Curr Pain Headache Rep. 2020 Mar 21; 24(5)19
  41. Gaul C, Eschalier A. Dose Can Help to Achieve Effective Pain Relief for Acute Mild to Moderate Pain with Over-the-Counter Paracetamol. The Open Pain Journal. 2018; 11:12-20

DISCLOSURES

Medical writing support was provided by Maria Carla Marrè Brunenghi, an independent medical writer, on behalf of Ma.CRO Lifescience Srl. The publication was supported by an unconditional grant by Angelini Pharma S.p.A

Conflict of Interests: The authors declares they have no conflicts of interest in this work.

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