The clock, the mouth and the ladder

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The IASP stresses the need to distinguish between pain and nociception, the latter referring to the neural processing of noxious stimuli by the central and peripheral nervous systems, such as those induced by tissue injury or extreme temperatures. The IASP cautions that activity in sensory neurons cannot definitively indicate the presence of pain.1

Photograph of a woman who has abdominal pain
According to a South African study, one in five South African are living with chronic pain. Women have a higher risk of chronic pain (20.1%) compared to men (15.8%). Image: Shutterstock

Additionally, the IASP states that it is importance to respect an individual's verbal expression of their pain experience. Verbal communication is acknowledged as just one of many behavioural cues indicative of pain. Thus, the inability to articulate pain verbally does not discount the possibility of experiencing pain, a phenomenon observed in both humans and non-human animals.1

Pain is classified into three types:2

  1. Nociceptive pain: This type of pain is caused by damage to body tissues. It is typically sharp, aching, or throbbing in nature and is often localized to the site of tissue damage. Examples include pain from cuts, burns, fractures, or inflammation.
  2. Neuropathic pain: Neuropathic pain arises from damage or dysfunction of the nervous system, particularly the peripheral or central nerves. It can manifest as shooting or burning pain, tingling, or numbness. Conditions such as diabetic neuropathy, post-herpetic neuralgia (shingles), and nerve compression injuries can cause neuropathic pain.
  3. Neuroplastic pain: This type of pain is related to changes in the nervous system, particularly in response to chronic musculoskeletal conditions such as arthritis or repetitive strain injuries. It involves alterations in neural pathways and processing, leading to increased sensitivity and pain perception.2


Understanding the different types of pain is crucial for appropriate management and treatment strategies. Effective pain management often involves a multidisciplinary approach that addresses both the physical and psychological aspects of pain.2

Chronic versus acute pain

The IASP defines acute and chronic pain as:

  1. Acute pain has a sudden onset, short duration (lasts from a few minutes to <6-months) and is clearly associated with a cause (eg injury, surgery, illness, trauma, or painful medical procedures).3
  2. Chronic pain is defined as pain that lasts or recurs for >3 months. In chronic pain syndromes, pain can either be the primary concern or a prominent symptom that necessitates specialised treatment and attention. Conditions like fibromyalgia or nonspecific low-back pain may be regarded as chronic primary pain, where pain itself is considered a distinct condition. Conversely, in six other subgroups, pain is secondary to an underlying disease. These subgroups include chronic cancer-related pain, chronic neuropathic pain, chronic secondary visceral pain, chronic posttraumatic and postsurgical pain, chronic secondary headache and orofacial pain, and chronic secondary musculoskeletal pain. In these cases, pain is initially perceived as a symptom of an underlying condition and is categorised as chronic secondary pain.4


According to a South African study, one in five South African are living with chronic pain. Women have a higher risk of chronic pain (20.1%) compared to men (15.8%). Furthermore, the prevalence of chronic pain showed an increase from 11.3% in the age group of 15- to 24-years to 34.4% among individuals aged >65-years. The body regions most commonly affected by chronic pain were the limbs, with a prevalence of 43.6%, followed by the back, with a prevalence of 30.5%.5

Pain causes: Nurture, nature or both?

The perception of pain is shaped by a complex interplay between environmental factors and genetic predispositions. Environmental influences, including psychological, social, and cultural factors, significantly impact pain perception and behaviour. 6

Psychological factors such as past pain experiences, emotional state, and coping mechanisms, as well as social factors like socioeconomic status and cultural beliefs, contribute to variations in pain sensitivity and response across individuals and populations.6

Cultural factors play a significant role in how pain is expressed and managed, with differences observed in coping styles and attitudes toward pain medication among different cultures.6

Ethnic disparities in pain sensitivity and tolerance highlight the influence of socioeconomic disparities, chronic stress, and limited social support on pain experiences among minority populations.6

Demographic factors such as gender and age also influence pain perception, with women generally reporting higher pain intensity and being at greater risk for chronic pain disorders compared to men. Ageing can affect pain sensitivity due to physiological and psychosocial changes.6

Lifestyle habits such as exercise, smoking, and alcohol consumption further impact pain perception, with varying effects on pain severity and chronicity.6

Psychosocial and biobehavioural factors, including personality traits, mood disorders, and sleep disturbances, significantly influence pain perception and behaviour, with catastrophising linked to heightened pain intensity and maladaptive responses.6

Clinical factors, including disease-related variables and treatment outcomes, also play a role in pain perception and management, emphasising the importance of addressing acute pain to prevent its transition into chronic pain.6

Research into the molecular genetics of pain has shown genetic risk factors that contribute to pain phenotypes across species. Heritability studies have provided insights into the genetic basis of pain perception, highlighting distinct genetic mechanisms for processing different types of stimuli.6

Monogenic pain disorders caused by mutations in specific genes underscore the role of rare genetic variants in pain conditions and offer potential therapeutic targets.6

Candidate gene association studies have identified numerous genes contributing to different types of pain, suggesting shared genetic pathways underlying various pain conditions. The influence of genetic variants extends beyond functional pain disorders to impact acute and chronic pain responses in diverse conditions.6

Evoked pain is a valuable tool in dissecting the genetic basis of clinical pain phenotypes, with genetic studies revealing variability in pain sensitivity influenced by specific genes. Investigations into analgesic response have identified genetic variations affecting drug metabolism and response, with implications for pain management.6

While numerous pain-related genes have been identified, genome-wide association studies offer promise in identifying novel genetic variants associated with pain phenotypes, paving the way for personalised pain management approaches.6

Advances in sequencing technologies hold potential for uncovering rare mutations contributing to extreme pain phenotypes, further enhancing our understanding of the genetic underpinnings of pain.6

The 5 As of pain management

A widely used comprehensive strategy for addressing persistent pain is the five As of pain management:7

  1. Analgesia
  2. Activities of daily living
  3. Adverse effects
  4. Affect
  5. Aberrant drug-related behaviors (eg addiction).


Shifts in these five domains over the course of opioid treatment indicate potential complications, therapy shortcomings, and increased vulnerability to advancing toward opioid dependence and addictive disorders.7

The World Health Organisation’s (WHO) analgesic ladder, is based on three key principles:8

  1. By the clock
  2. By the mouth
  3. By the ladder.


In essence this means timely administration, oral delivery, and stepwise escalation.8

The WHO’s analgesic ladder recommends:8

Step 1: Mild pain: Non-opioid analgesics such as nonsteroidal anti-inflammatory drugs (NSAIDs) or acetaminophen with or without adjuvants.

Step 2: Moderate pain: Weak opioids (hydrocodone, codeine, tramadol) with or without non-opioid analgesics and with or without adjuvants.

Step 3: Severe and persistent pain: potent opioids (morphine, methadone, fentanyl, oxycodone, buprenorphine, tapentadol, hydromorphone, oxymorphone) with or without non-opioid analgesics, and with or without adjuvants.

FDC tramadol/paracetamol offers swift action and long-lasting pain relief

Tramadol and paracetamol are some of the most prescribed painkillers in the world. Fixed-dose Tramadol/paracetamol is also available in a fixed-dose combination (FDC) with paracetamol for the symptomatic treatment of moderate to severe pain. FDC tramadol/paracetamol is a swiftly acting, long-lasting, multi-faceted pain reliever, exhibiting efficacy and generally favourable tolerability among patients living with moderate to severe pain.9,10,11

Across several meticulously conducted clinical trials, both single and multiple doses of tramadol/paracetamol demonstrated efficacy in alleviating pain in adult patients following minor surgical procedures, those suffering from various forms of musculoskeletal pain (acute, subacute, or chronic), painful diabetic peripheral neuropathy, or migraine pain.11

Studies have also shown that FDC tramadol/paracetamol is effective as an adjunctive analgesic for individuals experiencing moderate to severe musculoskeletal pain (such as osteoarthritis or rheumatoid arthritis pain) despite ongoing NSAID and/or disease-modifying antirheumatic drug therapy.11

Furthermore, in patients contending with postoperative pain, ankle sprain discomfort, or subacute lower back pain, the analgesic prowess of tramadol/paracetamol surpassed that of paracetamol, generally matched or exceeded tramadol alone, and generally equalled ibuprofen or FDCs such as hydrocodone/paracetamol, codeine/paracetamol, and codeine/paracetamol/ibuprofen.11

Additionally, the analgesic effectiveness of tramadol/paracetamol did not significantly deviate from that of gabapentin in patients enduring chronic pain associated with diabetic peripheral neuropathy.11

Notably, tramadol/paracetamol exhibited no additional tolerability concerns compared to its individual components, and overall, its tolerability profile closely resembled that of other active comparators (be they fixed-dose combinations or single agents). However, incidences of certain adverse events were lower among tramadol/paracetamol recipients compared to those receiving active comparators.11


The rapid onset and long-lasting efficacy of FDC tramadol/paracetamol make it a viable option for patients living with moderate-to-severe pain caused by  various conditions, including postoperative recovery, musculoskeletal disorders, diabetic neuropathy, and migraines. Studies have shown its comparable or superior performance to widely utilised analgesics such as paracetamol, standalone tramadol, and even ibuprofen. Additionally, the favourable tolerability profile and limited occurrence of adverse events associated with FDC tramadol/paracetamol reinforce its status as a valuable therapeutic option for individuals seeking effective pain relief.


  1. Raja SN, Carr DB, Cohen M, et al. The revised International Association for the Study of Pain definition of pain: concepts, challenges, and compromises. Pain, 2020.
  2. Acute pain. [Internet]. Available at:,to%20less%20than%20six%20months.
  3. Subedi M, Bajaj S, Maushmi SK, Mayur YC. An overview of tramadol and its usage in pain management and future perspective. Biomedicine & Pharmacotherapy, 2019.
  4. Treede RD, Rief W, Barke A, et al. Chronic pain as a symptom or a disease: the IASP Classification of Chronic Pain for the International Classification of Diseases (ICD-11). Pain, 2019.
  5. Kamerman PR, Bradshaw D, Laubscher R, et al. Almost 1 in 5 South African adults have chronic pain: a prevalence study conducted in a large nationally representative sample. Pain, 2020.
  6. Belfer I. Nature and nurture of human pain. Scientifica (Cairo), 2013.
  7. Maumus M, Mancini R, Zumsteg DM, Mandali DK. Aberrant Drug-Related Behavior Monitoring. Ochsner J, 2020.
  8. Anekar AA, Hendrix JM, Cascella M. WHO Analgesic Ladder. [Updated 2023 Apr 23]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-. Available from:
  9. Sabi Boun S, Omonaiye O, Yaya S. Protocol for a scoping review study on the prevalence and public health consequences of non-medical use (NMU) of tramadol in Africa. PLoS One, 2023.
  10. Ayoub SS. Paracetamol (acetaminophen): A familiar drug with an unexplained mechanism of action. Temperature (Austin), 2021.
  11. Dhillon S. Tramadol/paracetamol fixed-dose combination: a review of its use in the management of moderate to severe pain. Clin Drug Investig, 2010.

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