Mechanism-based pain diagnosis

Ideal for pain management is to measure symptoms and to treat pain mechanisms1

Pain management should ideally measure symptoms and treat pain mechanisms. But the identification of the underlying mechanisms is difficult as symptoms are not always equivalent to the mechanism.1

Usually, pain patients are analyzed on the basis of common causes of disease. This approach groups patients into categories, e.g. (low) back pain or osteoarthritic pain. Although such an approach is helpful, it ignores the possibility that diverse mechanisms may underlie the pain.

Mechanism-based pain diagnosis can be difficult, but physicians should attempt to define the types of pain that the patient is experiencing:
  • Nociceptive
  • Neuropathic
  • Pain related to inflammatory conditions
  • Pain with no clear stimulus or associated damage
(1)
Woolf CJ, Max MB. Mechanism-based pain diagnosis: issues for analgesic drug development. Anesthesiology. 2001;95:241-9.

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Clinical Mechanisms of Pain

Key types of pain

Pain is not a homogeneous sensory entity, it is individual.

Primary types of pain include:

  • Nociceptive pain: pain in response to a noxious stimulus on nociceptor
  • Neuropathic pain: spontaneous pain and hypersensitivity to pain in association with damage to or a lesion of the nervous system
  • Inflammatory pain: spontaneous pain and hypersensitivity to pain in response to tissue damage and inflammation
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Mechanism-orientated treatment rationale

Pain can either be purely nociceptive, purely neuropathic or both

Pain can be caused by multiple, different mechanisms, and pain is processed and modulated by multiple excitatory and inhibitory systems.

Better understanding of pain mechanisms is important:

  • To develop a mechanism-orientated approach to the treatment of pain conditions1
  • To optimize pharmacological treatment of pain and increase the potential for treatment success2

Analgesia may be obtained by drugs that either:

  • Block excitatory transmission or
  • Activate inhibitory systems
(1)
Woolf CJ, Max MB. Mechanism-based pain diagnosis: issues for analgesic drug development. Anesthesiology. 2001;95:241-9.
(2)
Davis MP. What is new in neuropathic pain? Support Care Cancer. 2007. 15(4):363-372

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Summary: non-opioids and opioids

Different pharmacological groups are effec- tive at different points in the pain pathway

Non-opioid analgesics
Non-steriodal anti-inflammatory drugs (NSAIDs)/Cyclooxygenase-2 inhibitors:
  • NSAIDs inhibit the enzyme cyclooxygenase, and consequently prostaglandin synthesis. These agents act mainly peripherally.
Other non-opioid analgesics:
  • Paracetamol and metamizol must be set apart from NSAIDs because of their predominantly central prostaglandin inhibition. They do not act antiinflammatory. Their mechanism of action has still not been fully explained.
Opioids
Opioids act at two sites in the spinal cord:
  • They reduce pain signal transmission by activating pre-synaptic opioid receptors. This leads to reduced intracellular cyclic adenosine monophosphate (cAMP) concentration, decreased calcium ion influx and thus inhibits the release of excitatory neurotransmitters (glutamate, substance P).
  • At the post-synaptic level, opioid-receptor binding evokes a hyperpolarisation of the neuronal membrane which decreases the probability of the generation of an action potential.
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Summary: anticonvulsants, TCAs and SNRIs

Different pharmacological groups are effec- tive at different points in the pain pathway

Anticonvulsants
  • Anticonvulsants inhibit the neuronal excitation and stabilize nerve membranes by blocking ion channels centrally.
Tricyclic antidepressants (TCAs)
  • TCAs inhibit the neuronal re-uptake of NA or 5-HT from the synaptic cleft – the resulting increased transmitter concentration affects central structures of pain processing
  • In addition, the increased NA and 5-HT levels intensify the descending pain inhibition pathway (although 5-HT can also facilitate pain).
Selective serotonin and noradrenaline re-uptake inhibitors (SNRIs)
  • SNRIs selectively inhibit the neuronal re-uptake of NA and 5-HT from the synaptic cleft – the resulting increased transmitter concentration affects central structures of pain processing
  • In addition, the increased NA and 5-HT levels intensify the descending pain inhibition pathway (although 5-HT can also facilitate pain)
  • Unlike TCAs, SNRIs do not have relevant affinity to adrenergic, cholinergic or histaminergic receptors (they are selective inhibitors) and thus do not evoke related side effects.
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Treatment of pain with neuropathic components

Classical pharmaceuticals in current pain management1

The analgesic potency of classical opioids in pain with a neuropathic component might be limited due to pathophysiological mechanisms.1

Sustained or repeated activation of the opioidergic system may lead to reduced opioid responsiveness and relative opioid analgesic tolerance.1
Therefore larger doses may are required to treat neuropathic pain than are needed to treat nociceptive pain. Higher doses, however, carry the risk of starting the Vicious Circle.2,3

  • No current medication on the market effectively addresses both neuropathic and nociceptive components1,2
  • Combination therapy or higher doses often result in decreased tolerability3
(1)
Davis MP. What is new in neuropathic pain? Support Care Cancer. 2007. 15(4):363-372
(2)
Raffa RB. Pharmacology of oral combination analgesics: rational Therapy for pain. J Clin Pharm Ther. 2001;26:257-264
(3)
Varrassi G et al. Pharmacological treatment of chronic pain - the need for CHANGE. Curr Med Res Opin 2010,26(5):1231-1245

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Rationale for combining pharmacological agents

Combination of pharmacological agents1

The rationale for combining pharmacological agents is that:
  • A combination of drugs provides multiple mechanisms of action which can simultaneously target multiple pain pathways
  • Using multiple drugs can potentially have a additive / synergistic effect
  • Drugs can be combined that have complementary pharmacokinetic profiles
  • A combination of drugs can achieve a comparable efficacy to, for example, higher doses of single agents, but with a more favourable side-effect profile
Example:
  • Opioids have a strong analgesic effect in nociceptive pain
  • Neuropathic pain is only partially responsive to opioids1
  • For treating pain with both a nociceptive and neuropathic component, an opioid may therefore be combined with antidepressants or anticonvulsants2
(1)
Davis MP. What is new in neuropathic pain? Support Care Cancer. 2007. 15(4:363-372)
(2)
Hanna M et al. Prolonged-release oxycodone enhances the effects of existing gabapentin therapy in painful diabetic neuropathy patients. Eur J Pain. 2008;12(6):804-813.

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Loose drug combination

Gabapentin + oxycodone vs. Gabapentin + placebo

The combination of classical opioids with co-analgesics is common for the pharmacological treatment of severe chronic pain conditions composed of both a nociceptive and a neuropathic component. However, there is still limited evidence for evaluation of benefits, and the risk of interaction and substance-specific side effects might be a limiting factor for combining two different substances:

  • The simultaneous administration of two drugs (combination) does not guarantee that they interact effectively, neither in analgesic effect nor in terms of side effects.
  • The combination of opioids with co-analgesics can be accompanied with an increased risk of side effects, which can start the Vicious Circle1,2
  • Combination therapy is accompanied with a higher likelihood of drug-drug interaction1,2
(1)
Hanna M et al. Prolonged-release oxycodone enhances the effects of existing gabapentin therapy in painful diabetic neuropathy patients. Eur J Pain. 2008;12(6):804-813.
(2)
Varrassi G et al. Pharmacological treatment of chronic pain - the need for CHANGE. Curr Med Res Opin 2010,26(5):1231-1245

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Fixed drug combinations

Combination of different pharmacological agents are common

Combination of different pharmacological agents are common and can either serve the purpose of addressing different underlying mechanisms or prevent / reduce side effects.

Examples of fixed drug combinations include:
  • Combination of low-dose opioid and non-opioid (e.g. codeine-paracetamol / tramadol-paracetamol )
  • Combination of opioid with antagonist for reduction of GI side effects (e.g. oxycodone-naloxone)
  • Combination of non-opioid and gastric protective agent for reduction of GI side effects (e.g. diclofenac-misoprostol)
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Rationale for a new analgesic class

Two mechanism in a single molecule

Two pain modulation systems are relevant in chronic pain.

  • Opiodergic and monoaminergic system

Simultaneous activation of both systems may result in analgesic synergy.1

Based on the relevance of these two pain modulating systems, there is a clear rational for the development of analgesic combining the two mechanisms of action, μ-opioid receptor agonism (MOR) and noradrenaline reuptake inhibition (NRI), which enhance the concentration of noradrenalin (NA) in synaptic cleft, thereby enhancing NA-mediated effects.

A new pharmacological drug class – MOR-NRI – reflects the unique pharmacological profile differentiating this compound from all other centrally acting analgesics:

  • Tapentadol is a novel, centrally acting analgesic combining two mechanisms of action μ-opioid receptor agonism (MOR) and noradrenaline reuptake inhibition (NRI) – in a single molecule.2
(1)
Tzschentke TM, Christoph T, Kögel B, et al. (-)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol hydrochloride (tapentadol HCl): a novel mu-opioid receptor agonist/norepinephrine reuptake inhibitor with broad-spectrum analgesic properties. J Pharmacol Exp Ther. 2007;323:265-76.
(2)
Kress H. (Editorial) Tapentadol and its two mechanisms of action: Is there a new pharmacological class of centrally acting analgesics on the horizon? Eur J Pain 2010, in press

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Quick check

Which of the following are potential benefits of combining analgesics with different modes of action to manage chronic pain? Select the response that is not correct.
Reduced potential for side-effects compared with high dose single agent therapy
Synergistic analgesic effects
Increased potential for drug interactions
Complementary pharmacokinetic profiles
Which of the following statements is correct?
Combination therapy always result in decreased tolerability
Current medications adresses both neuropathic and nociceptive components effectivley
Efficacy of classical opioids in neuropathic pain might be limited due to diversity of underlying pathophysiological mechanisms.
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Congratulations

Thank you for participating in the ninth basic module “Mechanism-orientated pharmacological management”. We hope you enjoyed it. The PAIN EDUCATION platform provides more eModules concerning pain therapy. If you like to, please continue with these eModules and check your knowledge.
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