Subcutaneous administration of paracetamol—Good local tolerability in palliative care patients: An observational study

Abstract

Background:

The subcutaneous route is widely used in both palliative care and geriatrics. Numerous compounds are administered by this route, including paracetamol. However, there is no recommendation on which to base this latter practice and, in the absence of published evidence, nothing is known regarding its local tolerability in palliative care patients.

Aim:

The main objective of this study was to assess the local tolerability of paracetamol when administered subcutaneously for analgesic or antipyretic purposes in patients hospitalized in the palliative care unit. The secondary objective was to identify the factors favoring the occurrence of local adverse events.

Design:

This is a prospective multicenter observational study (NCT02884609).

Participants:

Study conducted in 160 patients hospitalized in the palliative care units of three hospitals in metropolitan France from 2014 to 2017.

Results:

Of the 160 patients, 44 (28%) presented at least one non-serious local adverse event (edema in 29, erythema in 5, pain in 15, hematoma in 2, pruritus in 1, and local heat in 2). No serious adverse events were observed. Factors associated with the occurrence of local adverse events were younger age, administration in the arm and thorax, and a high number of daily administrations.

Conclusion:

This first ever study carried out on this subject reveals that subcutaneous administration of paracetamol in palliative care patients was well tolerated locally.

Keywords

Acetaminophen drug-related side effects and adverse reactions palliative medicine observational study

What is already known about the topic?

The subcutaneous route is widely used in palliative care and geriatrics.

Paracetamol is currently not recommended for subcutaneous use in the absence of validated references but is nonetheless classified in the category of drugs “used by some teams.”

What this paper adds?

No serious local adverse events were observed after subcutaneous administration of paracetamol.

Of the 160 patients, 44 (28%) had at least one non-serious local adverse event during the follow-up.

Edema represented the main non-serious adverse event followed by pain erythema.

Factors associated with the occurrence of local adverse events were younger age, administration in the arm and thorax, and a high number of daily administrations.

Implications for practice, theory, or policy

Subcutaneous administration of paracetamol seems well tolerated in palliative care patients.

However, further studies are needed to show that this practice, while well tolerated, is also effective.

Introduction

The subcutaneous route is widely used in both palliative care and geriatrics.^1,2 This mode of administration offers many advantages when other administration routes (oral, sublingual, rectal, or venous) are unreliable, unavailable, or unacceptable for the patient.^1,3,4

Several studies have recently reviewed the drugs that can be used subcutaneously.^1,3

Paracetamol is not mentioned¹ or is referred to as “non-evaluated.”³ The subcutaneous administration of paracetamol is nonetheless practiced since it is classified in the category of products that “some teams use.”¹ Moreover, a survey regarding the subcutaneous use of paracetamol in palliative care units (PCUs) in France revealed that it is used by 40% of the physicians responsible for these entities.⁵

Paracetamol has indeed appealing analgesic and antipyretic properties for the management of frail patients.^6,7 It allows limiting the use of aspirin, nonsteroidal anti-inflammatory drugs, or morphine, which displays significant side effects.^8,9

Given the existence of subcutaneous administration of paracetamol, and that such practice is not documented in the literature, we conducted a study the objectives of which were (1) to evaluate the local tolerability of subcutaneous-administered paracetamol in patients hospitalized in PCUs and (2) to identify the factors favoring the occurrence of local adverse events.

Materials and methods

Study design and population

This prospective multicenter observational study was conducted between 2014 and 2017 in patients hospitalized in the PCUs of three hospitals located in France.

According to French legislation applicable during the implementation of the study and consistent with a European directive,¹⁰ this observational study was approved by the French Advisory Committee on Information Processing in Health Research (CCTIRS, No. 16-083), authorized by the French National Data Protection Commission (CNIL, DR-2016-302), and registered at ClinicalTrials.gov under registration number NCT02884609.

Each patient was informed of the course of the study and gave verbal consent for inclusion and use of the data. In instances where the patient was unable to communicate, his or her support person (personne de confiance according to French legislation) or relatives were informed and gave verbal consent.

To participate in the study, the PCUs were required to already routinely use paracetamol by subcutaneous administration.

All adult patients hospitalized in the PCUs and requiring subcutaneous administration of paracetamol for analgesic or antipyretic purposes were included. Patients were not included in instances of (1) opposition to the use of the data collected for clinical research, refusal expressed either by the patient or by his or her relatives when the patient could not give his consent and (2) subcutaneous administration of paracetamol in the week prior to arrival in the PCUs.

Assessment criteria

The primary assessment criteria were the occurrence of local adverse events (pain, pruritus, edema, erythema, warm skin, hematomas, and vesicles) or serious local adverse events (skin ulcers, abscesses, and skin necrosis).

Local adverse events were assessed prior to the first injection as well as 30 min, 2 and 4 h after the first injection, and on a daily basis until the day after the discontinuation of use of the first subcutaneous administration site of paracetamol, regardless of the reasons for discontinuation of use of this first administration site and whether or not paracetamol subsequently continued to be administered on a different administration site.

Local adverse events were assessed as follows:

Pain was assessed using the numeric rating scale (NRS) for communicating patients and the Algoplus scale for non-communicating patients.¹¹

Pruritus was self-assessed by communicating patients, and scratching lesions were assessed by nurses for non-communicating patients.

Other local adverse events were investigated by the nurses.

Statistical analysis

The number of patients to be included was contingent on the need to be able to demonstrate rare adverse events. According to the literature,^12–16 an adverse event after subcutaneous drug administration was considered rare when observed in 2% of cases. Hence, a minimum of 149 patients were deemed necessary to obtain at least a 95% probability of observing at least one adverse event with an expected frequency of 2%. This sample yielded an accuracy of ±8% on the outcome measures.

Several factors potentially influencing the occurrence of local adverse events were gathered: age, gender, presence of other products at the administration site, mean number of other products, duration of use of the administration site, total number of injections of paracetamol, mean number of injections of paracetamol per day, injection site, cancerous or non-cancerous nature of the disease, paracetamol manufacturer, and inclusion center.

All compounds used at the same injection site as paracetamol were recorded and classified into three groups: (1) products not presenting an identified risk of local adverse events, (2) products with identified risk of local adverse events, and (3) products for which the risk of local adverse events was unknown.

In order to establish this classification, existing literature data were used.^1,2,12,17,18

Results

A total of 160 patients were included in this study, aged between 27 and 100 (median: 80) years. The main characteristics of the patients are summarized in Table 1.

Table 1.

Description of the study population (N = 160).

Characteristics	N (%)	Mean ± SD
Age (years)		77 ± 13
Gender (F)	70 (44)
Inclusion center
H	71 (44)
L	79 (49)
D	10 (6)
Pathology
Cancerous	119 (74)
Non-cancerous	41 (26)
Patients with communication disorders	86 (54)
Weight >50 kg	141 (88)
Paracetamol manufacturer
Macopharma	74 (46)
Braun	76 (48)
Panpharma	10 (6)
Injection site
Thigh	64 (40)
Abdomen	36 (23)
Arm	28 (18)
Thorax	14 (9)
Back	9 (6)
Missing data	9 (6)
Other products at the site of injection	132 (83)
Number of other products used at the site of injection		3.9 ± 1.8
Indication for paracetamol
Systematic	118 (74)
Induced pain	19 (12)
Antipyretic	10 (6)
Acute pain	13 (8)
Scale used for assessment of pain
Numeric rating scale	74 (46)
Algoplus	86 (54)

SD: standard deviation.

Paracetamol was administered at a dose of 1000 mg/injection if the patient’s weight was higher than 50 kg (141 patients); otherwise, the dosage was 500 mg/injection (19 patients).

Paracetamol was administered, either with other products on an existing subcutaneous access port (132 patients) or in isolation on a specific access port (28 patients).

The mean duration of use of the administration site for paracetamol was 2.3 ± 1.9 days and the mean assessment time for the occurrence of local adverse effects was 2.7 ± 2 days. The reasons for discontinuing the use of the first site of subcutaneous administration of paracetamol were as follows: change of injection site (60 patients, 38%), patient deceased (45 patients, 28%), appearance of a local adverse event (17 patients, 11%), change in the administration route (13 patients, 8%), accidental withdrawal of the catheter (8 patients, 5%), and return home (1 patient, 1%).

Over the course of the study, none of the patients presented serious local adverse events. Of the 160 patients, 44 (28%) had at least one non-serious local adverse event, either within the first 4 h following the first injection or during the monitoring of the administration site. Edema was observed in 29 patients, erythema in 5 patients, pain in 15 patients, hematoma in 2 patients, pruritus in 1 patient, and local heat in 2 patients. Table 2 shows the distribution of the local adverse events recorded during follow-up.

Table 2.

Local adverse events (at the injection site) during follow-up.

Event	D030 min	D02 h	D04 h	D1(N = 139)	D2(N = 119)	D3(N = 72)	D4(N = 42)	D6(N = 14)
Local adverse event	7 (4)	2 (1)	2 (1)	23 (14)	19 (16)	9 (13)	2 (5)	1 (7)
Pain (NRS or Algoplus ⩾4)	1 (1)	0 (0)	0 (0)	9 (6)	5 (4)	2 (3)	0 (0)	0 (0)
Pruritus	1 (1)	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)
Edema	6 (4)	0 (0)	2 (1)	13 (9)	16 (13)	4 (6)	2 (5)	1 (7)
Erythema	1 (1)	2 (1)	1 (1)	2 (1)	2 (2)	2 (3)	0 (0)	0 (0)
Hematoma	0 (0)	0 (0)	0 (0)	0 (0)	1 (1)	2 (3)	0 (0)	0 (0)
Heat	2 (1)	0 (0)	0 (0)	0 (0)	2 (2)	0 (0)	0 (0)	0 (0)

NRS: numeric rating scale.

In nine patients (6%), adverse events occurred within 4 h after the first subcutaneous injection of paracetamol. Of the 139 patients followed at least 1 day after the first subcutaneous administration of paracetamol, 38 (27%) had at least one non-serious local adverse event.

The management of these non-serious local adverse events was always straightforward, with occasionally a change in administration site, but never by discontinuing the subcutaneous use of paracetamol.

Factors associated with the occurrence of a non-serious adverse event after subcutaneous injection of paracetamol were as follows: administration in the arm or thorax, higher number of daily injections, and younger age (Table 3).

Table 3.

Factors associated with the occurrence of a non-serious local adverse event (AE) during follow-up after subcutaneous injection of paracetamol.

Factors	Patients who presented an AE (N = 44)	Patients who did not present an AE (N = 116)	p value
Age (years)	73 ± 15	78 ± 12	0.01
Gender (F)	19 (43)	51 (44)	0.86
Presence of other products at the administration site	40 (91)	92 (79)	0.10
Mean number of other products	3.9 ± 1.7	4.0 ± 1.9	0.81
Duration of use of the administration site (days)	2.8 ± 1.3	3.1 ± 2.2	0.35
Total number of injections	6.3 ± 4.4	7.2 ± 7.0	0.32
Mean number of injections per day	3.3 ± 1.3	2.7 ± 1.5	0.02
Center			0.06
H	24 (55)	47 (41)
L	20 (45)	59 (51)
D	0 (0)	10 (9)
Injection site			<0.001
Thigh	8 (18)	56 (48)
Abdomen	8 (18)	28 (24)
Arm	14 (32)	14 (12)
Thorax	9 (20)	5 (4)
Back	2 (5)	7 (6)
Missing data	3 (7)	6 (5)
Cancerous disease	33 (75)	86 (74)	0.99
Paracetamol manufacturer			0.13
Macopharma	22 (50)	52 (45)
Braun	22 (50)	54 (47)
Panpharma	0 (0)	10 (9)

Presence of other products at the administration site was not associated with the occurrence of a non-serious adverse event. The products used at the same subcutaneous administration site as paracetamol are summarized in Table 4 and classified according to the level of risk of local adverse events.

Table 4.

Drugs used on the same subcutaneous injection site as paracetamol, classified according to the level of risk of local adverse event.

Products	N (%)
Products with identified risk of local adverse events
Ceftriaxone	21 (13)
KCl	3 (2)
Octreotide	2 (1)
Tramadol	1 (1)
Products not presenting an identified risk of local adverse event
Midazolam	55 (34)
Methylprednisolone	54 (33)
Oxycodone	49 (31)
NaCl	43 (27)
Bionolyte	29 (18)
Furosemide	26 (16)
Morphine	26 (16)
Scopolamine butylbromure	21 (13)
Omeprazole	20 (13)
Metoclopramide	12 (8)
Sufentil	7 (4)
Nefopam	3 (2)
Clonazepam	2 (1)
Levetiracetam	1 (1)
Prostigmin	1 (1)
Products whose risk of local adverse event is unknown
Pantoprazole	32 (20)
Phloroglucinol	14 (9)
Alizapride	9 (6)
Tiapride chlorhydrate	8 (5)
Esomeprazole	3 (2)
Hydroxyzine	1 (1)

Discussion

One of the key findings of this study is that, over the entire follow-up period, no patient presented a serious adverse event, whether ulceration, necrosis, or abscess.

Edema represented the main non-serious adverse event followed by pain and erythema, which is consistent with prescribers’ perception of this practice.⁵ Such side effects are also often highlighted when various compounds are administered subcutaneously,^14,19,20 including during hydration.¹² Subcutaneous administration of antibiotics can also be responsible for local reactions such as skin necrosis.^21–23 Such complications were not observed in this study.

The greater occurrence of adverse events when injections were made in the arm or thorax can be explained by a lower volume of diffusion at these sites than in the thigh or abdomen. The effect of the number of daily injections may be explained by an increased volume of injected paracetamol.²⁴

The higher incidence of adverse events in younger patients is more difficult to explain. The clinical relevance of this statistical difference may nonetheless be questioned, with the mean age increasing from 73 to 78 years.

Our study shows that paracetamol was often administered in combination with strong opioids, although it may not provide added benefit above regular opioids^25,26 mainly at high dose,²⁷ and although opioid-sparing effect of paracetamol in patients with cancer pain remains uncertain.²⁵ Paracetamol was also often used systematically, with the objective to alleviate pain due to cancer, although the role of paracetamol in the management of cancer pain still remains controversial.²⁸ It will be probably necessary to assess paracetamol indications in PCUs to avoid abusive generalization of use.

Our study has several limitations. First, some data were missing (injection site for 9 patients, reason for discontinuing the use of the first site for 12 patients, incomplete pain assessment during the first injection for 14 patients, lack of pain evaluation during daily monitoring for 14 patients, and lack of adverse event assessment the day after the discontinuation of first site use for 13 patients). As a result, the occurrence of local pain and delayed adverse events may have been underestimated.

Second, while no serious adverse events were observed in our study, it is possible that such events might occur after the subcutaneous injection of paracetamol without our study being able to highlight their occurrence if their frequency is below 2%, as this was the chosen frequency for defining a rare adverse event in this study.

Finally, the design of this study did not allow for the efficacy of subcutaneously administered paracetamol to be assessed because it was often administered in patients with little or no pain at the time of administration and with other analgesics. A study comparing the pharmacokinetics of paracetamol when administered subcutaneously versus intravenously in healthy volunteers would be of great interest.

Conclusion

Our study shows that the subcutaneous administration of paracetamol is well tolerated locally in palliative care patients hospitalized in PCUs. It would thus appear appropriate for teams already using this approach to continue this practice, while teams that do not could consider using paracetamol subcutaneously when no other route is available, reliable, or acceptable for the patient. However, further studies are needed to show that this practice, while well tolerated, is also effective.

Footnotes

Acknowledgements

The authors thank the following investigators who participated in this study: Raphaël Alluin, Anne-Cécile Bourjal, Stéphane Picard, Elise Piot, Claire Reneaux, and Jean-François Villard. They also thank Laura Saez for her feedback and revision of the manuscript.

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

References

Morisson

Vassal

Rochas

et al . Drugs used subcutaneously in palliative care: review of the literature and recommendations. Méd Palliat 2012; 11(1): 39–49.

Fonzo-Christe

Vukasovic

Wasilewski-Rasca

et al . Subcutaneous administration of drugs in the elderly: survey of practice and systematic literature review. Palliat Med 2005; 19(3): 208–219.

Picon

Duwig

Administration des médicaments par voie sous-cutanée; une alternative intéressante en gériatrie. Repères en Gériatrie 2011; 13(109): 143–146.

Graham

Syringe drivers and subcutaneous sites: a review. Eur J Palliat Care 2006; 13(4): 138–141.

Masson

Leheup

BF.

Use of subcutaneous acetaminophen in palliative care unit in France. Méd Palliat 2018; 17(1): 3–9.

Graham

Scott

Day

RO.

Tolerability of paracetamol. Drug Saf 2005; 28(3): 227–240.

Bannwarth

Péhourcq

Pharmacologic basis for using paracetamol: pharmacokinetic and pharmacodynamic issues. Drugs 2003; 63(2): 5–13.

Tremblay Nguyen

Noublanche

Barre

et al . Pain management in elderly people. La Revue De Gériatrie 2012; 37(3): 173–183.

Pickering

Pain, opioïds and the elderly. Cah Année Gérontol 2014; 6: 21–25.

10.

Claudot

Alla

Fresson

et al . Ethics and observational studies in medical research: various rules in a common framework. Int J Epidemiol 2009; 38(4): 1104–1108.

11.

Rat

Jouve

Pickering

et al . Validation of an acute pain-behavior scale for older persons with inability to communicate verbally: Algoplus. Eur J Pain 2011; 15(2): 198.e1–198.e10.

12.

Bruera

Legris

Kuehn

et al . Hypodermoclysis for the administration of fluids and narcotic analgesics in patients with advanced cancer. J Pain Symptom Manag 1990; 5(4): 218–220.

13.

Walker

Watanabe

Lawlor

et al . Subcutaneous clodronate: a study evaluating efficacy in hypercalcemia of malignancy and local toxicity. Ann Oncol 1997; 8(9): 915–916.

14.

Thomas

Yocum

Haller

et al . The INFUSE-Morphine IIB study: use of recombinant human hyaluronidase (rHuPH20) to enhance the absorption of subcutaneous morphine in healthy volunteers. J Pain Symptom Manag 2009; 38(5): 673–682.

15.

Barbot

Venisse

Rayeh

et al . Pharmacokinetics and pharmacodynamics of sequential intravenous and subcutaneous teicoplanin in critically ill patients without vasopressors. Intensive Care Med 2003; 29(9): 1528–1534.

16.

Hardy

Quinn

Fazekas

et al . Randomized, double-blind, placebo-controlled study to assess the efficacy and toxicity of subcutaneous ketamine in the management of cancer pain. J Clin Oncol 2012; 30(29): 3611–3617.

17.

Maison

Gastine

Peter-Derex

et al . Subcutaneous administration of levetiracetam in geriatrics. Rev Neurol (Paris) 2015; 171(4): 398–399.

18.

Lopez-Saca

Vaquero

Larumbe

et al . Repeated use of subcutaneous levetiracetam in a palliative care patient. J Pain Symptom Manag 2013; 45(5): e7–8.

19.

Adams

Cruz

Deachman

et al . Focal subdermal toxicity with subcutaneous opioid infusion in patients with cancer pain. J Pain Symptom Manag 1989; 4(1): 31–33.

20.

Cools

Berkhout

De Bock

GH.

Subcutaneous morphine infusion by syringe driver for terminally ill patients. Age Ageing 1996; 25(3): 206–208.

21.

Taillandier

Manigand

Fixy

et al . Skin necrosis induced by subcutaneous gentamicin. Presse Med 1984; 13(25): 1574–1575.

22.

Bricaire

Castaing

Pocidao

et al . Pharmacokinetics and tolerance of ceftriaxone after subcutaneous administration. Pathol Biol 1988; 36(5): 702–705.

23.

Forestier

Gros

Peynaud

et al . Ertapenem administered intravenously or subcutaneously for urinary tract infections caused by ESBL producing Enterobacteriaceae. Med Maladies Infect 2012; 42(9): 440–443.

24.

Bartz

Klein

Seifert

et al . Subcutaneous administration of drugs in palliative care: results of a systematic observational study. J Pain Symptom Manag 2014; 48(4): 540–547.

25.

Nikles

Mitchell

Hardy

et al . Single-patient multiple crossover studies to determine the effectiveness of paracetamol in relieving pain suffered by patients with advanced cancer taking regular opioids: a pilot study. Palliat Med 2016; 30(8): 800–802.

26.

Nabal

Librada

Redondo

et al . The role of paracetamol and nonsteroidal anti-inflammatory drugs in addition to WHO Step III opioids in the control of pain in advanced cancer. Palliat Med 2012; 26(4): 305–312.

27.

Israel

Parker

Charles

et al . Lack of benefit from paracetamol (acetaminophen) for palliative cancer patients requiring high-dose strong opioids: a randomized, double-blind, placebo-controlled, crossover trial. J Pain Symptom Manage 2010; 39(3): 548–554.

28.

Mercadante

Giarratano

The long and winding road of non steroidal antinflammatory drugs and paracetamol in cancer pain management: a critical review. Crit Rev Oncol Hemat 2013; 87(2): 140–145.