Multimodal analgesia in moderate-to-severe pain: a role for a new fixed combination of dexketoprofen and tramadol

Figures & data

Figure 1. Correlation between NSAID anti-inflammatory/analgesic potency ratio in experimental models and clinical analgesic activity in a model of post-surgical dental pain. Graphical elaboration from Cashman⁵⁶.

Table 1. Summary of the pharmacodynamic features of the opiod agonists, usually combined with non-opioid analgesics.

Drug	Opioid receptor selectivity			Additional mechanisms(s)
	μ	κ	δ
Weak opioids
Codeine	+	+	–	None
Tramadol	+	+	–	5-HT & NA re-uptake inhibition
Strong opioids
Morphine	+++	++	+	None
Oxycodone	++	+++	+	None

Table 2. Summary of the pharmacokinetic features of the opiod agonists, usually combined with non-opioid analgesics.

Drug	Bioavailability (%)	Protein binding	Half-life (h)	Hepatic catabolism	Active metabolite (s)
Weak opioids
Codeine (Inactive pro-drug)	40–70	90	2–3	CYP2D6 Glucuronidation	Morphine (10%) Norcodeine, C6-G
Tramadol (Active drug)	68–72	20	5–6	CYP2D6	O-dimethyltramadol
Strong opioids
Morphine	20–30	20–36	2–4	Glucuronidation	M-3-G M-6-G
Oxycodone	60–80	45	2–3	CYP3A4 CYP2D6	Noroxycodone Oxymorphone

All four compounds are excreted mainly by the renal route.

Figure 2. Clinical study in a dental pain model showing the best analgesic efficacy of the dexketoprofen-tramadol combination in a 1:3 ratio. Percentage of patients showing response (≥ 50% max TOTPAR) over 6 h post-dose (Primary end-point). Maximum TOTPAR corresponds to the theoretical maximum possible time-weighted sum of the PAR scores, measured on a 5-point VRS (0 = none to 4 = complete). Graphical elaboration from Moore et al.⁴⁸

Figure 3. Fixed-dose combination dexketoprofen/tramadol mechanism of action. Different modes of action contribute to dexketoprofen/tramadol analgesic FDC efficacy. A synergy between central analgesic action, peripheral analgesic effect, and anti-inflammatory activity underlies the multimodal analgesia provided by the fixed-dose combination dexketoprofen/tramadol. 5-HT: 5-hydroxytryptamine (serotonin); AA: arachidonic acid; COX: cyclo-oxygenase; GABA: γ-amino-butyric acid; MOR: μ-opioid receptor; NA: noradrenaline; PG: prostaglandin.

Table 3. Percentage of pain intensity (PI) responders (achievement of mean pain intensity VAS <40 mm) at rest over the first 8 h and percentage of patients using rescue medication (RM) over 24 h, during the multiple dose phase in clinical trials with DKP/TRAM FDC.

	FDC DKP/TRAM	DKP 25 mg	TRAM 100 mg	p-value
Pain after hysterectomy
Percentage of PI responders (mean PI-VAS <40)	65	46	41	.001 vs DKP <.001 vs TRAM
Percentage of patients using RM over 24h	4.4	11	10	.01 vs DKP .021 vs TRAM
Pain after total hip arthroplasty
Percentage of PI responders (mean PI-VAS <40)	77	67	66	.055 vs DKP .029 vs TRAM
Percentage of patients using RM over 24h	7.0	17	19	<.001 vs DKP <.001 vs TRAM

Data from DKP/TRAM FDC clinical trials^78,79.

Cashman JN. The mechanisms of action of NSAIDs in analgesia. Drugs 1996;52(Suppl 5):13-23

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McQuay HJ, Moore RA, Berta A, et al. Randomized clinical trial of dexketoprofen/tramadol 25 mg/75 mg in moderate-to-severe pain after total hip arthroplasty. Br J Anaesth 2016;116:269-76

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