Severe acute pain remains a major problem associated with trauma-related injuries and surgery procedures. Acute pain persists as an unavoidable outcome and all efforts should be performed to manage the impact of painful conditions in a patient’s recovery ^[1][2][3][1,2,3]. Besides the emotional impact, the suffering induced by untreated acute pain can result in physical problems such as myocardial ischemia, impaired wound healing, delayed gastrointestinal motility, and poor respiratory effort ^[3][4][3,4]. Also, poor respiratory effort can result in atelectasis, hypercarbia, or hypoxemia and thus contribute to a higher incidence of post-operative pneumonia [3].

Among analgesics, opioids are considered the “gold standard” for the treatment of painful conditions after surgery procedures. Nevertheless, they offer only moderate efficacy in relieving pain during movement while having relevant side effects, such as nausea, vomiting, and a high risk of addiction ^[4][5][6][4,5,6].

Multimodal pain management guidelines have proposed the implementation of non-opioid analgesic procedures aiming to avoid the use of opioid substances in monotherapy or at least reduce the doses used for acute pain treatment [7].

The combination of non-opioid analgesics, mainly paracetamol (or acetaminophen) with non-steroidal anti-inflammatory drugs (NSAIDs), is one of the most reported multimodal approaches used in clinical practice ^{[2][8][9][10]}[2,8,9,10]. The guidelines for acute pain management issued by the American Society of Anesthesiologists (ASA) recognized the effective and well-established use of combined paracetamol and NSAIDs for several types of pain ^{[2][3][5][9][11][12]}[2,3,5,9,11,12]. Also, the Enhanced Recovery After Surgery (ERAS) Society guidelines recommend a multimodal approach through the administration of paracetamol and NSAIDs in combination ^[13][14][13,14]. This kind of combination has been a central focus of ERAS protocols since it reduces the need for opioid drugs, diminishing simultaneously painful and inflammatory conditions ^{[2][7][9][11][15]}[2,7,9,11,15].

In general, fixed-dose combinations (FDCs) offer the opportunity to improve the therapeutic response in people where monotherapy approaches have failed [16]. Also, FDCs could contribute markedly to pain management in low-income countries where the availability of opioid drugs is extremely limited and non-opioid analgesics are generally cheap. Indeed, in 2011, 89% of globally available opioids were consumed only by the USA (United States of America), Canada, the UK (United Kingdom), and Australia [1].

Ibuprofen/paracetamol FDC in tablets are available in the US and some European markets as over-the-counter (OTC) products. Also, in some European countries, but not in the US, ibuprofen/paracetamol FDCs are approved for intravenous (IV) administration.

Since the parenteral administration of analgesic entities allows for a rapid onset of action and pain management in patients that are unable to intake oral formulations ^[3][7][3,7], parenteral FDCs of non-opioid analgesics composed of NSAIDs may play a decisive role in the treatment of acute pain due to the possibility of simultaneously solving some limitations related to monotherapy regimens [16].

Pain pathways are a complex system where a noxious stimulus is converted into a neural signal resulting in the perception of an unpleasant experience. Beyond the negative impact at the emotional level, acute pain deeply challenges patients’ mobilization and may compromise surgery outcomes [10].

Due to the complexity of pain physiology, a single analgesic drug able to completely suppress pain perception remains an impossibility. To accomplish such a task, more effective and satisfying results could be achieved by using multimodal analgesia approaches ^{[2][3][4][10]}[2,3,4,10].

Multimodal analgesia entails the administration of different pharmacological agents with different mechanisms of action to obtain improved analgesic outcomes than those obtained via single-drug administration. At the same time, a potential synergic relationship between the combined drugs may allow for the reduction of drug doses and thus induce fewer side effects ^{[2][3][12][17]}[2,3,12,17].

Multimodal analgesia aims to avoid the use of opioids or at least significantly reduce their effective doses [13]. At the same time, it is related to the early mobilization and discharge of patients, fewer readmission rates, and improved patient satisfaction [17]. Also, many works have reported multimodal analgesia as a fundamental approach to minimizing unnecessary opioid use and a relevant tool to manage the risk of opioid addiction ^[3][17][3,17]. In the clinical context, multimodal analgesia has been recommended in numerous pain management guidelines issued by several renowned medical institutions such as the ASA, American Academy of Pain Medicine (AAPM), Orthopaedic Trauma Association (OTA), and Doctors Without Borders (MSF), among others. For instance, in 2015, a partnership between the AAPM, ASA, US Department of Veterans Health Administration, and Department of Defense resulted in the definition of new clinical practice guidelines for post-operative pain management [18]. Based on these guidelines, the multimodal approach using NSAID combinations with paracetamol is presented as a strong recommendation with high-quality evidence [18]. Additionally, over the last few years, ERAS protocols are becoming the benchmark standards for enhancing post-operative recovery [14]. In these guidelines, multimodal analgesia has now established itself as the “gold standard” of perioperative analgesic care due its prominent implementation as an essential component in pain treatment [14].

Several classes of drugs can be used in combination. Non-opioid analgesics (including NSAIDs), N-methyl-D-aspartate (NMDA)-receptor antagonists, gabapentinoids, α₂-receptor agonists, local anesthetics, and selective serotonin reuptake inhibitors (SSRIs) are some examples of drug classes that are being used as analgesic entities ^{[2][4][7][10][12][14]}[2,4,7,10,12,14]. Notably, some of these classes of drugs were originally developed and approved not to treat painful conditions but to treat other pathologic conditions such as depression, Alzheimer’s disease, epilepsy, and hypertension. The analgesic activity of this heterogeneous group of pharmacological entities is explained by the physiology of pain and its mechanisms of transmission [17].

Pain can be divided into two major types: nociceptive and neuropathic. The first one has physiological functions and is related to noxious stimuli and tissue damage. The second one is precepted when the somatosensory system itself is damaged and is recognized as a pathological condition ^[17][19][17,19]. Based on the type, location, and patient perception of pain, one or more pain pathways can be targeted using analgesic combinations [17].

Parenteral analgesics allow for the administration of drugs when more convenient routes are not clinically available ^[3][7][3,7]. The most common parenteral routes of administration are IV, intramuscular (IM), and subcutaneous (SC) [20]. IV analgesia in one of the most common approaches used in the management of acute pain induced by surgical procedures ^[14][21][14,21]. Also, the IM and SC routes are commonly employed for the treatment of acute pain; however, after surgery, they should not be considered first-line options since the poor perfusion and delayed distribution of the drugs is a risky possibility and can result in the occurrence of inadequate analgesia or the late occurrence of side effects [20]. Although IM and SC formulations may be appropriate for patients without IV access and with the oral route unavailable, IV administration is believed to provide the fastest relief ^{[3][4][22][23][24][25]}[3,4,22,23,24,25]. However, when compared to other routes of administration, the costs related to the use of IV forms are higher and with no benefits in terms of pain control [20].

Despite the evident advantages of the use of parenteral analgesics, their development and manufacture can be challenging and expensive [26]. For instance, the poor water solubility of ibuprofen and diclofenac can result in the development of unstable products; post-administration crystallization may lead to the formation of aggregates and emboli in blood vessels ^[26][27][26,27]. In contrast, metamizole is very soluble in aqueous solutions but stability issues may also be raised [28].

Despite the large number of non-opioid analgesics available on the market, there is yet a lack of options concerning parenteral solutions. Until 2020 in the US, only parenteral formulations of paracetamol, ibuprofen, and ketorolac had been approved for post-operative pain management in monotherapy regimens [7]. In 2020, an IV formulation of meloxicam was approved by the US Food and Drug Administration (FDA), but in December 2022, its commercialization was discontinued since, according to Baudax Bio (market applicant), “despite having distinct benefits as the first and only once-daily non-opioid IV analgesic, market conditions are not favorable for the introduction and commercialization of a new pain management product in the hospital market” [29]. Concerning the European market, the number of approved parenteral non-opioid analgesics is larger; however, their availability is different between sovereign countries (Table 1).

The parenteral administration of some analgesic drugs can impact the pharmacologic profile (i.e., pharmacokinetics and pharmacodynamics). For instance, the pharmacologic activity of paracetamol depends on its route of administration. When administered orally, paracetamol will suffer first-pass metabolism and be converted into p-aminophenol in the liver and then into N-(4-Hydroxyphenyl) arachidonylamide (AM404) in the brain. The AM404 is a potent agonist of the transient receptor potential vanilloid type 1 (TRPV1), a low-affinity ligand of the cannabinoid receptor type 1 (CB₁), an anandamide membrane transporter blocker, and a cyclooxygenase (COX) inhibitor [30]. When paracetamol is taken intravenously, it is spared from the first-pass process and the biosynthesis of AM404 is less extensive [31]. Also, intravenously, the maximum plasma concentration of paracetamol is greater and achieved earlier. Since paracetamol enters the central nervous system (CNS) through passive diffusion, the gradient concentration between the plasma and CNS tissues is a very important factor for its infiltration into the CNS ^[23][24][23,24].

In contrast to paracetamol, metamizole pharmacology seems not to be impacted by the route of administration since the bioconversion of metamizole in their active metabolite occurs extensively in the stomach and plasma ^[32][33][32,33].

Concerning NSAIDs, oral administration is as efficacious as intravenous intervention since their oral bioavailability is commonly very high ^[34][35][34,35]. The most evident advantage of the intravenous administration of NSAIDs is their fast onset when compared with enteric routes ^[34][35][34,35]. For instance, the maximum plasma concentration achieved after the IV administration of ibuprofen is twice as high as the concentration achieved through oral routes and earlier administration (IV: 0.11 h vs. oral: 1.5 h) [36]. Since the mechanism of action and the pharmacology of NSAIDs are independent of the route of administration, an earlier achievement of maximum plasma concentration commonly results in a fast onset ^[21][37][38][21,37,38].

The mechanism of action of paracetamol is not completely understood. However, it is probably mediated through COX-inhibition in the central nervous system ^[13][39][40][13,39,40]. Research has suggested that paracetamol acts as an inhibitor, particularly for COX inhibitor-3, a COX-1 isoenzyme mainly expressed in the central nervous system ^[13][39][13,39]. Also, its analgesic mechanism could be related to the activation of the descending serotonergic pathway, the indirect activation of CB₁ receptors, and the inhibition of nitric oxide pathways in the central nervous system ^[3][17][3,17].

The paracetamol metabolite AM404 also plays a very relevant role concerning analgesic activity. Like paracetamol, its mechanism of action is not completely understood; however, it seems to act in the blockade of the neuronal uptake of anandamide and neuronal sodium channels [40].

Peripherally, although paracetamol exerts COX-1 and 2 inhibition in in vitro assays, the expected anti-inflammatory activity is not observed in vivo since the high concentrations of peroxide in inflamed tissues hinder the paracetamol activity [3].

The IV administration of paracetamol and NSAIDs allows for a faster effect onset and greater peak plasma concentration compared to oral administration ^[4][7][40][4,7,40]. Additionally, IV administration seems to be less hepatotoxic than the oral route due to the absence of first-pass phenomena [4]. Remarkably, no evidence of hepatotoxicity was observed after administration of 5 g of paracetamol via IV across 24 h in healthy subjects, a higher dosage than recommended [4].

Paracetamol is the most common analgesic used in multimodal analgesia since its administration is generally well tolerated, with a minimal side effect profile [14]. In Europe and the US, IV formulations of paracetamol have been available on the market since late 2002 and November 2010, respectively ^[4][25][31][4,25,31]. The common formulation is 1000 mg/100 mL and the brands available are listed on the FDA website and on the list of nationally authorized medicinal products (PSUSA/00002311/201705) issued by the European Medicines Agency (EMA) ^[41][42][41,42].

Despite the numerous IV formulations of paracetamol available on the market, their development was always challenging due to the poor stability of paracetamol [43]. Indeed, during degradation, paracetamol is converted by hydrolysis into 4-aminophenol, which is rapidly converted into the hepatotoxic substance N-acetyl-p-benzoquinone imine (NAPQI). At the same time, oxidation reactions occur, producing degradation products. To avoid degradation, the synthesis of active pharmaceutical ingredients (APIs) and the manufacturing of a parenteral finished product should be performed under optimal pH values (from 5 to 6) and low oxygen media (bubbling nitrogen) [43].

Metamizole (or dipyrone) is a non-acidic analgesic like paracetamol but belongs to the group of phenazones [44]. Like paracetamol, metamizole is a common analgesic and antipyretic drug but with low anti-inflammatory activity. It is generally well tolerated and can treat several painful conditions including post-operative pain, headaches, migraines, neuropathic pain, cholic pain, and cancer pain ^{[44][45][46][47][48]}[44,45,46,47,48]. For post-surgery purposes, metamizole is a more effective analgesic than paracetamol and at least as effective as NSAIDs [47].

As monotherapy and due to its presumably favorable safety profile, metamizole is preferred over NSAIDs [44]. However, metamizole has been related to cases of severe neutropenia and agranulocytosis (myelotoxicity) and, due to this fact, it was banned from the market in some countries such as the US, the UK, Sweden, Canada, Australia, Norway, and India ^{[46][47][48][49][50][51][52]}[46,47,48,49,50,51,52]. Nevertheless, metamizole is still available in some European and South American countries ^{[44][47][48][49]}[44,47,48,49]. Indeed, the incidence of metamizole-induced myelotoxicity is controversial and varies widely between studies. Yet, some works point to a risk of approximately 1:1602 and a relative risk of 3.03 ^[46][53][46,53]. Clinical studies with low enrolment and some other limitations like ethnicity factors could explain the significant differences reported by authors about the incidence of adverse events associated with metamizole ^[51][52][54][51,52,54].

The mechanisms of action are not completely understood; however, in the literature, metamizole is presented as a prodrug, while its metabolites act at both peripheral and central levels ^[44][47][48][44,47,48]. 4-N-methyl-aminoantipyrine (4-MAA) is the main metabolite in plasma ^[47][55][56][47,55,56]. This metabolite is biosynthesized non-enzymatically from metamizole in the gastrointestinal tract and its extensive absorption results in a bioavailability close to 100% ^[47][55][56][47,55,56].

Some authors have reported the inhibition of COX activity to be the main mechanism of action of metamizole. However, metamizole metabolites seem to directly block the hyperalgesia induced by prostaglandin E2 (PGE2) and isoprenaline through a COX-independent mechanism ^[44][47][48][44,47,48]. Interestingly, like paracetamol, metamizole presents COX inhibition activity in vitro (mainly COX-2 activity) but exhibits a weak anti-inflammatory ability and low gastrointestinal toxicity in humans [48]. Recently, Gomes F. et al. [56] reported that metamizole directly blocks nociceptor sensitization via the activation of the NO signaling pathway. The same authors hypothesized that metamizole promotes the engagement of the PI3Kγ/AKT/nNOS/cGMP pathway, which results in the hyperpolarization of the primary sensory neuron terminals and decreases neuronal excitability [56]. Also, Gonçalves do Santos G. et al. [57] have reported that the 4-MAA anti-hyperalgesic effect depends on κ-opioid receptor activation, acting as a morphine-like drug ^{[52][56][58][59]}[52,56,58,59]. Despite all of this, metamizole is yet classified incorrectly as an NSAID by some authors [50].

The mechanism responsible for agranulocytosis is not fully understood; however, some authors excluded a direct toxic effect of metamizole by pointing to an immunoallergic reaction as a possible hypothesis ^[50][53][50,53]. In the presence of heme iron, 4-MAA forms reactive electrophilic entities that are toxic for granulocyte precursors. This can occur mainly when there is a depletion of the cellular adenosine triphosphate (ATP) pool [47].

In contrast to paracetamol, metamizole is very soluble in water; however, it is chemically unstable ^[28][60][28,60]. Since metamizole is hydrolyzed rapidly and non-enzymatically to its active metabolite, 4-MAA, its stability verified in commercial liquid formulations is achieved using high concentrations of metamizole. The concentration is the major factor in the hydrolysis of metamizole and thus increasing the concentration of metamizole decreases the hydrolysis rate [61].

In the European market, metamizole for parenteral use is commonly available in vials of 500 mg/1 mL, 1 g/2 mL, or 2 g/5 mL for IV or IM use. The list of products available in European countries can be found on the list of nationally authorized medicinal products (PSUSA/00001997/202103) issued by the EMA.

NSAIDs are the most consumed drugs worldwide and the most common option available for the treatment of mild-to-moderate inflammatory pain without an additive effect [62]. The main and better-understood mechanism of action of NSAIDs is the inhibition of peripheral COX-1 and COX-2, two enzymes that play a crucial function in the production of pro-inflammatory prostaglandins ^[2][39][2,39]. Other additional mechanisms in the central nervous system are being proposed based on in vitro and animal experiments, without clear evidence of their occurrence in humans [11]. A central action by NSAIDs in humans is unlikely, or at least negligible, due to the pharmacokinetic profile of NSAIDs since their low distribution volume may reveal the slow or inadequate penetration of NSAIDs in the CNS [11].

As in the case of paracetamol, NSAIDs are also a key element in multimodal analgesia since they can provide superior analgesia with opioid-sparing and with fewer side effects such as nausea, vomiting, and unwanted sedation [14]. As cited previously, despite the large number of NSAIDs approved in the US and Europe, they are not all available in parenteral formulations. Currently, there is a lack of IV NSAIDs available on the market and there is a need for the development of new IV NSAID-based formulations [29]. Unfortunately, the very low market quote (February 2020–December 2022) and recent IV meloxicam discontinuation (Anjeso) from the US market may indicate that there is not a market available for new parenteral pain killers.

Table 1 presents all the parenteral NSAIDs available in the US and Europe. The number of NSAIDs authorized in Europe is larger; however, not all USA-approved products are also approved in Europe. Ibuprofen and ketoprofen are available for parenteral administration in Europe and the US. However, some differences still exist. Concerning ibuprofen, in the US, ampoules and flasks with 800 mg/8 mL and 800 mg/200 mL are available, while in Europe, only large-volume formulations exist. The maximum dose of ibuprofen is higher in the US (800 mg) than in Europe (600 mg). Also, small differences are observed when comparing ketorolac formulations available in the US and Europe; however, in both cases, the drug can be administered via IV or IM (Table 1).

Aspegic^® (acetylsalicylate), Xefo^® (lornoxicam), Neo-Indusix^® (tenoxicam), and Liometacen^® (indomethacin) are only available in Europe and are presented as freeze-dried products. The freeze-drying process is technically challenging, expensive, and yields fragile and hygroscopic products. However, in the case of less soluble drugs, such as indomethacin, tenoxicam, and lornoxicam, it can avoid the undesired crystallization of drugs during their storage ^[63][64][65][63,64,65]. Concerning acetylsalicylate formulation, although its salts are commonly soluble in water, freeze-drying is useful due to the extensive hydrolysis of salicylic salts in aqueous media [66].

Most NSAIDs share the same therapeutic indications; however, some of them are recommended predominantly for specific painful conditions. According to Table 1, the listed NSAIDs may be sorted into three groups: NSAIDs indicated predominantly for the treatment of musculoskeletal-system-related pain, NSAIDs indicated for the treatment of postoperative pain/post-traumatic-related pain, and NSAIDs indicated for the treatment of unclear painful conditions. Nevertheless, in the case of piroxicam and meloxicam, their therapeutic indications seem to be more restricted since in their Summary of Product Characteristics (SPCs), the first-line use of these products is discouraged due to their safety profiles ^[67][68][67,68].

All conventional NSAIDs are weak acids and, when they are taken orally, their molecules adopt uncharged conformations due to the strongly acidic environment of the stomach ^[69][70][69,70]. The uncharged state of the molecules allows for their rapid absorption through the gastric surface epithelium [69]. Since NSAIDs present generally high bioavailability after oral administration, the parenteral route is only recommended when less invasive routes are not available ^[34][35][71][34,35,71]. In contrast with paracetamol, where parenteral administration reduces hepatotoxicity, there is not clear evidence of the superior efficacy and safety of NSAIDs parenterally administered ^[35][71][35,71].

NSAID	Formulations	Route of Administration	Indications	Brands a	Countries with Marketing Authorization d
Ibuprofen	800 mg/8 mL 800 mg/200 mL	IV	Management of mild-to-moderate pain and moderate-to-severe pain in adults. Also, it is indicated for the reduction of fever in adults [72].	Caldolor®	US
Ketorolac	15 mg/1 mL 30 mg/1 mL	IV/IM	Short-term management of moderate-to-severe acute pain, including pain following operative procedures [73].	Toradol® b	US
Acetylsalicylate	500 mg/5 mL (freeze-dried)	IM/IV	Symptomatic treatment of pain in rheumatology, traumatology, oncology, surgery and anaesthesiology, post-operatively, and in preparation for exams. Also used in the symptomatic treatment of fever [74].	Aspegic®	BE, HU, and PT
Dexketoprofen	50 mg/2 mL 25 mg/2 mL	IM/IV	Symptomatic treatment of acute pain of moderate-to-severe intensity when oral administration is not appropriate, such as post-operative pain, renal colic, and lower back pain [75][76][75,76].	Ketesse® Keral® Auxilen® Dekenor® Morsadex®	DE, AT, SK, SI, ES, EE, FI, FR, GR, NL, HU, IE, LV, LT, MT, PL, CZ, and RW
	50 mg/100 mL	IV		Dexketoprofen B. Braun®	ES
Diclofenac	75 mg/3 mL c 50 mg/1 mL 25 mg/1 mL	IV/IM	IM use is effective in acute forms of pain, including renal colic, exacerbations of osteo- and rheumatoid arthritis, acute back pain, acute gout, acute trauma and fractures, and post-operative pain. In IV use, it is indicated for the treatment or prevention of post-operative pain in the hospital setting [77].	Voltaren® Voltarol® Fenil-V® Akis® plus Dicloin® Diclac® Almiral®	DE, AT, BE, BG, SK, SI, ES, EE, FR, FI, GR, NL, HU, IE, IT, LV, LT, MT, PL, PT, GB, CZ, RW, and SE
Etofenamate	1000 mg/2 mL	IM	Indicated in painful and acute inflammatory situations in rheumatology, traumatology, and post-operatively [78].	Rheumon® Traumon®	DE, AT, GR, HU, PT, and RW
Ibuprofen	600 mg/100 mL c 400 mg/100 mL 200 mg/50 mL	IV	Indicated in adults for the short-term symptomatic treatment of acute moderate pain and fever. IV route is clinically justified when other routes of administration are not possible [79].	Ibuprofen B. Braun® Solibu®	DE, AT, BE, BG, DK, SK, SI, ES, EE, FI, NL, HU, IE, LV, LT, PL, PT, GB, CZ, RW, and SE
Indomethacin	50 mg/2 mL 25 mg/2 mL (freeze-dried)	IV	Indicated to reduce (acute) pain due to inflammation of the muscles and muscle joints (musculoskeletal system) [80].	Liometacen®	IT
Ketoprofen	100 mg/2 mL c	IM	Indicated for rheumatoid arthritis, osteoarthritis ankylosing spondylitis, and acute episodes of gout. The injectable form is especially indicated for the treatment of acute attacks with a predominance of pain [81].	Profenid® Rofenid® Ketonal® Orudis®	BE, SK, SI, ES, FR, IT, LV, LT, PL, PT, CZ, and RW
Ketorolac	50 mg/5 mL 30 mg/1 mL c 10 mg/1 mL	IM/IV	It is indicated for the short-term management of moderate-to-severe acute post-operative pain. Treatment should only be initiated in hospitals. The maximum duration of treatment is two days [82].	Toradol® Taradyl®	BE, DK, ES, EE, FI, GR, IS, IT, LV, LT, PT, GB, RW, and SE
Lornoxicam	8 mg/2 mL (freeze-dried)	IM/IV	Short-term relief of acute mild-to-moderate pain [83].	Xefo®	SK, GR, HU, and RW
Meloxicam	15 mg/1.5 mL	IM	Short-term treatment of symptomatic acute exacerbations of rheumatoid arthritis and ankylosing spondylitis when other routes of administration are not appropriate [68].	Movalis® Melox® Mobic®	SK, EE, FR, GR, HU, IT, LV, LT, MT, PL, PT, and RW
Piroxicam	20 mg/1 mL	IM	Symptomatic relief of osteoarthritis, rheumatoid arthritis, and ankylosing spondylitis [67].	Feldene® Flexase®	DE, BE, ES, FR, HU, PL, and PT
Tenoxicam	20 mg/3 mL c (freeze-dried)	IM/IV	Indicated for patients considered unable to take oral tenoxicam for the relief of pain and inflammation in osteoarthritis and rheumatoid arthritis and for the short-term management of acute musculoskeletal disorders including strains, sprains, and other soft-tissue injuries [84].	Neo-Indusix®	GR, GB, and RW